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Brain Res Rev. Author manuscript; available in PMC 2008 December 1.
Published in final edited form as: Brain Res Rev. 2007 December ; 56(2): 283–321.
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Behavioral Functions of the Mesolimbic Dopaminergic System: an Affective Neuroethological Perspective
Antonio Alcaro1,3, Robert Huber1, and Jaak Panksepp1,2 1 Department of Biological Sciences and J.P. Scott Center for Neuroscience, Mind & Behavior, Bowling Green State University, Life Science Building, Bowling Green, OH, 43403, USA 2 Department of VCAPP, Center for the Study of Animal Well-Being, College of Veterinary Medicine, Washington State University, Pullman, WA 99163, USA 3 Santa Lucia Foundation, European Centre for Brain Research (CERC), Via del Fosso di Fiorano 65, 00143 Rome, Italy
The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, in cognitive processes. Functional theories have emphasized DA's involvement in the orchestration of goal-directed behaviors, and in the promotion and reinforcement of learning. The affective neuroethological perspective presented here, views the ML-DA system in terms of its ability to activate an instinctual emotional appetitive state (SEEKING) evolved to induce organisms to search for all varieties of life-supporting stimuli and to avoid harms. A description of the anatomical framework in which the ML system is embedded is followed by the argument that the SEEKING disposition emerges through functional integration of ventral basal ganglia (BG) into thalamocortical activities. Filtering cortical and limbic input that spread into BG, DA transmission promotes the “release” of neural activity patterns that induce active SEEKING behaviors when expressed at the motor level. Reverberation of these patterns constitutes a neurodynamic process for the inclusion of cognitive and perceptual representations within the extended networks of the SEEKING urge. In this way, the SEEKING disposition influences attention, incentive salience, associative learning, and anticipatory predictions. In our view, the rewarding properties of drugs of abuse are, in part, caused by the activation of the SEEKING disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect. The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors.
Keywords Mesolimbic; Dopamine; Motivation; Reward; Accumbens; Addiction
Correspondence to: Antonio Alcaro, Ph.D., Santa Lucia Foundation, European Centre for Brain Research (CERC), Via del Fosso di Fiorano 65, 00143 Rome, Italy. [email@example.com] or Jaak Panksepp, Ph.D, Department of VCAPP, Center for the Study of Animal Well-Being, College of Veterinary Medicine, Washington State University, Pullman, WA 99163, USA. Tel. USA 509-335-5803, Fax. 509-335-4650 [firstname.lastname@example.org]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Alcaro et al.
1.1. The mesolimbic dopamine (ML-DA) system
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The ML-DA system (Fig.1) has received considerable attention due to its involvement in a range of psychological processes and neuropsychiatric diseases. In fact, after the development of a DA theory of schizophrenia (Carlsson, 1974;1978;Snyder, 1972;Meltzer & Stahl, 1976), additional ML-DA hypotheses have been proposed to explain addiction (Wise & Bozarth, 1981;1987;Koob, 1992), attention deficit hyperactivity disorder (ADHD) (Oades, 1987;Levy, 1991; Russel, 2000), depression (Willner, 1983a,1983b,Dailly et al., 2004) as well as global behavioral activation (Gray, 1995) ranging from response persistence to behavioral compulsions (Salamone & Correa, 2002;Everitt & Robbins, 2005). Localized electrical brain stimulation studies (Olds & Milner, 1954; Heath, 1964, Olds, 1977; Wauquier & Rolls, 1976) have implicated the ML-DA in positive rewarding states (Wise, 1978; 1981; Wise & Rompre, 1989) as well as in appetitive motivated behaviors (Panksepp, 1971, 1981a, 1982; 1986, 1998; Blackburn et al., 1987; 1989; Berridge & Robinson, 1998; Ikemoto & Panksepp, 1999). Since DA is also released in response to aversive stimuli and stress (Abercombie et al., 1989; Puglisi-Allegra et al., 1991; Rouge-Pont et al., 1993; Pruessner et al., 2004), it appears to promote generalized behavioral arousal under both positive as well as negative emotional conditions, perhaps in terms best conceptualized as the seeking of safety (Ikemoto & Panksepp, 1999). Moreover, the ML-DA system has recently been recognized for its role in the determination of personality traits, including “novelty” or “sensation” seeking (Bardo et al., 1996; Zuckerman, 1990), “extraversion” (Depue & Collins, 1999), and “impulsivity” (Cardinal et al., 2004). Current interpretations of ML-DA functions diverge with respect to emphasis on unconditioned or behavioral priming effects (motivational theories) versus conditioned effects (learning theories). The “psychomotor activation” hypothesis (Wise & Bozarth, 1987), the “behavioral activation system” hypothesis (Gray, 1995), the “behavioral facilitation” hypothesis (Depue & Collins, 1999), the “SEEKING system hypothesis” (Panksepp, 1981; 1998; Ikemoto & Panksepp, 1999), the “wanting” hypothesis (Berridge & Robinson, 1998), and the “effortregulation” hypothesis (Salamone & Correa, 2002; Salamone et al., 2003) all acknowledge a motivational interpretation of ML-DA functioning. They share a common perspective based on the classic distinction between appetitive and consummatory phases of motivated behaviors (Sherrington, 1906; Craig, 1918), and with relatively minor differences, consider the DA system as a fundamental drive for the expression of appetitive-approach behaviors. The “reinforcement” (Fibiger, 1978; White & Milner, 1992; Everitt & Robbins, 2005) and the “reward” hypotheses (Wise, 1978; Wise & Rompre, 1989; Schultz, 1997; 1998; 2001; Spanagel & Weiss, 1999; Di Chiara, 2002; Wise, 2004), on the other hand, have largely focused on DA as a learning mediator. While motivational theories are interested in the proactive actions of DA transmission on future behaviors, learning theories tend to consider retroactive effects on strengthened associations among past events. Although modern incentive motivation concepts view rewards as promoters of motivational arousal and increased behavioral readiness (Bolles, 1972; Binda, 1974; Toates, 1986; Berridge & Robinson, 1998), learning theories consider that the “most important role of DA in incentive motivation is historical; it is the stamping-in of stimulus-reward association that has established incentive motivational value for previously neutral stimuli” (Wise, 2004). Multiple attempts to integrate motivational and learning perspectives of ML-DA transmission have been pursued (e.g., Berridge, 2004; Toates, 2004; Koob, 2004), but a coherent evolutionary-ethological view of how brain DA promotes certain types of unconditional psychobehavioral tendencies is typically missing in most formulations. Therefore, a
Brain Res Rev. Author manuscript; available in PMC 2008 December 1.
Alcaro et al.
comprehensive hypothesis integrating new findings with earlier literature on rewarding electric brain stimulation has yet to emerge. In our opinion, such needed integration may be achieved by postulating a role of ML-DA in modifying primary-process emotional behaviors1 and internal affective states (Panksepp, 1998, 2005)2. In fact, emotions and affects have repercussion both on the way animals act in the world and learn through experience. As extensively described in previous works (Panksepp, 1981; 1998; Ikemoto & Panksepp, 1999), ML-DA promotes the emergence of the SEEKING emotional disposition3, which we envision as an affective urge that characterizes all motivated behaviors. This view has been around as long as the more recent incentive-salience and reinforcement-type theories, but has been typically ignored by those committed to behaviorist learning paradigm. 1.2. Functional anatomy of the mesencephalic DA projections In mammals, most DA-containing neurons clustered within three major mesencephalic groups: A8 cells in the retrorubral field, A9 cells in the substantia nigra (SN) and A10 cells in the ventral tegmental area (VTA) (Dahlstrom & Fuxe, 1964; Ungerstedt, 1971; Lindvall & Bjorklund, 1974; Fallon & Moore, 1978; German et al., 1983; Arsenault et al., 1988; German & Manaje, 1993). Similar organizations of DA cell bodies have been demonstrated in reptiles (Smeets et al., 1987; Smeets, 1988; Gonzalez et al., 1994) and birds4 (Smits et al., 1990; Durstewitz et al., 1999). In addition, less dense aggregations of DA neurons inhabit the supramammillary region of the hypothalamus, the dorsal raphe and the periaqueductal gray (Swanson, 1982; Gaspar et al., 1983). Morphological characteristics, anatomical locations, ascending projections and their associations with arousal functions, have led many to assign DA neurons to the classical “reticular formation” (Moruzzi & Magoun, 1949; Schiebel & Schiebel, 1958; Leontovich & Zhukova, 1963). Placed within the context of the reticular activating system (Parvizi & Damasio, 2001), DA neurons are sensitive to various global states of organisms, and their ascending projections modulate brain arousal in accordance with those states (Geisler & Zahm, 2005). The mesencephalic DA cell groups (A8; A9 and A10) lack clear anatomical boundaries, develop in parallel from common embryonic tissues (Olson & Seiger, 1972; Fallon & Moore, 1978; Hu et al., 2004), and partly overlap in their projection fields (Nauta et al., 1978). Their axons project largely to structures located in the anterior part of the forebrain, and modulate the activity of cognitive-executive reentrant circuits between the cortical mantle and the BG (Alexander et al., 1986; Kalivas et al., 1999) (Fig. 2). Such circuits are involved in the organization of practically all motivated behaviors, both highly flexible and more automatic. It is thought that BG-thalamocortical circuits produce adaptive behavioral flexibility, while their dysregulation underlies a whole plethora of neuropsychiatric diseases, from depression to obsessive-compulsive disorders, from addiction to Parkinson, etc. (Swerdlow & Koob, 1987; Robbins, 1990; Deutch, 1993; Kropotov & Etlinger, 1999; Jentsch et al., 2000; Graybiel & Rauch, 2000; Joel, 2001; Groenewegen, 2003). Resembling a spiraling, functional organization (Zahm and Brog, 1992), a special type of “state” process, information flow appears to exist between different loops of such circuitries with feed-forward processing from
1An emotional behavior is a flexible and coherent adaptive response to biologically relevant stimuli. It has an instinctual and inherited basis, but is different from other instincts because of its plastic nature and its strong subjective—affective aspects. All the emotional behaviors are constituted by a wide array of behavioral and autonomic responses coordinated as an emotional operating system (or emotional command system) constituted of specific neural circuits within the brain (Panksepp, 1998). 2An affective state is the basic subjective feeling characteristic of primary-process homeostatic drives, emotions and the resulting sustained moods. 3In this paper we will continue to use the convention of capitalizing the SEEKING disposition indicating that a specific neurodynamic state is activated and the SEEKING system to help highlight that a functional neural system is being discussed. Please also note that capitalizations are used to i) avoid part-whole confusions, ii) to alert readers to the claim that these may be necessary brain systems for those types of emotional behaviors and feelings although by no means sufficient for all the emotional manifestations. 4Comparative studies in vertebrates have demonstrated the loss of some dopamine (and noradrenaline) cell groups in amniotes compared with anamniotes, especially in the hypothalamic periventricular region (Smeets & Gonzales, 2000). Brain Res Rev. Author manuscript; available in PMC 2008 December 1.
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Kiyatkin & Rebec. and their influence on brain activity may be described with the concept of “dynamic attractors” (Freeman. which are essential infrastructures for intentional behaviors5. and functional criteria (Bernheimer et al. 1985... One hypothesis posits that DA regulatory function increases the signal-to-noise ratio and enhances the efficacy of neural networks in elaborating biologically significant signals (Rolls et al. 1998. remains unclear. 1996. 2004). Mogenson. Graybiel. Llinas et al. 2003. procedural patterns associated with the expressions of exploring and approach behaviors (locomotion.e. The reverberation 5Intentions literally mean to tend to something. Wise & Bozarth. 1989. 1999). 1996. motivated movements. intentional behaviors are intrinsically driven by impulses of neural activity organizing a specific type of behavioral sequence even before specific objects come to be represented as the final goals. to executive and motor circuits (Heimer & Van Horsen. 1989. 2003). head movements. 1985. 2000.. Carli et al. How can DA affect behavioral and psychological processes? DA-receptor activated molecular pathways have been partially unraveled (Greengard et al. Neurodynamic sequences are repetitive sequential activity patterns reverberating across specific areas and circuits of the brain.3. 1984. 2006). 2000. Although DA cell groups form an anatomical continuum. 2001.. 2000). However. DA neurons thereby act as an intermediary of limbic-emotional and motivational action outflow (Haber et al.. et al. for understanding how behavioral and psychological arousal is processed in the nervous system. 1980b). Ciompi & Panksepp. 2000. Here.. and in the process of “reward” than the laterally situated NS-DA fields (Papp & Bal. 1987. the signal-to-noise ratio hypothesis explains how behavioral and motivational arousal processes may be linked to specific cognitive or perceptual representations. DeFrance et al. these rhythms may be accompanied by the release of neurodynamic instinctual sequences. 2004.. available in PMC 2008 December 1. 2001b) and thereby influences the way specific external information is processed within the brain (Mesulam. 2005). Joel & Weiner. The ML-DA system (Fig. Ikemoto & Panksepp. Blackburn et al. Jog et al. they have been called “avalanches” (Begs & Plenz.. DA interacts with fast synaptic transmission (Greengard. 2004. the ML-DA system has been differentiated from the nigrostriatal (NS) DA system on the basis of anatomical. Page 4 limbic regions (especially medial frontal areas).. in flexible-emotive behaviors.. because goal-directed behaviors presuppose the explicit representation of the goal. Lee et al. Freeman. 2005. controls procedural aspects of movements and motivated behaviors as it reaches more dorsal areas of BG. 1999.1).. sniffing. Nicola et al. 1999. Greengard. large-scale energetic states of the brain. instead of electrical activity of single neurons. Magill et al. 1. Brown. need to be considered (Steriade. we generally choose to use the concept of intentional behaviors instead of goal-directed behaviors. Author manuscript. In their primary-process form. 1987. The sequential patterns favored by DA in ventral BG-thalamocortical circuits may relate to an instinctual drive to seek life-supportive aspects of the environment and to actively escape those aspects that could be destructive. DA modulates global-field dynamics. 1997. intentional behaviors are sustained initially by the unconditional tendency of basal forebrain/BG circuits to complete a neurodynamic sequence once it has been activated. 1974). 2003). 2001a). is more ancient in brain evolution than the more laterally situated NS-DA circuitry.. where behavioral and cognitive habits are learned. 1998). NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . In our view. and it has been more clearly implicated in the regulation of intentional. 2003. Haber. 2004).). saccades. but epigenetically refined. desynchronizes cortical-derived oscillatory rhythms and promotes high-frequency waves along the gamma band within BGthalamocortical circuits (Brown & Mardsen. they are endogenously produced instinctual activities that naturally predispose generalized (initially objectless) action urges to evolve behaviorally towards more specific goal-directed responses. These neurodynamic sequences are evolutionarily intrinsic.Alcaro et al.. Ungerstedt et al. Berridge & Robinson. 1998. On the contrary. In sum. Brain Res Rev. in contrast. The NS-DA system. but the precise mechanisms by which DA influences behavioral and psychological phenomena. situated more medially in the brain. 2000. stored and expressed (Hornykiewicz. Based on in vivo and in vitro single-cell studies. As a modulator of neural activity.. i. 1973. Recently. 1979.
the diencephalon and the basal forebrain. 2000. 2000. 1999. 1990. and how do they interact with informational processes? New neurodynamic approaches. Jones. 1951. primary-process “intentions in action” get transformed into learning and thought-related “intentions to act” (Panksepp. As the main source of the basic sleep-wake cycle. Moreover.. In particular. 2003). Brown. Brain Res Rev. Sharot et al. 2004). DA neurons are sensitive to various global states of the organism and their ascending projections modulate brain arousal in accordance with those states. Page 5 of such sequential patterns within brain circuits change the individual's attitude towards the environment. 2002. Ciompi & Panksepp. Placed within the context of the reticular activating system (Parvizi & Damasio. Author manuscript. and BG are involved in the expression of sequential. 2005). 2) Internal procedural sequences—Behavior is not limited to learning and associative processes. 1950. 1986). In this way. since most areas innervated by DA projections sends feedback to DA neurons via direct and indirect pathways. This establishes a variety of expectancy states that energize and coordinate the anticipation of life supporting events with characteristic reward seeking behavioral tendencies (Panksepp. 1998). In particular. Kandel. are essential for almost aspects of goal-directed learning. Levy et al. promoting the SEEKING disposition to dominate the motivational landscape of the organism (Panksepp. such constraints emerge substantially from the influences that subcortical brain structures exert over neocortical functions (MacLean. behavioral and mental activities.Alcaro et al.. speciesspecific movements. 2003. it promotes waking arousal as well as behavioral inhibition (Jones. Magill et al. 2004. p287). basal forebrain. In vertebrates.. that grant organisms intrinsic behavioral urges. 2005). consisting in a “neural continuum with overlapping dendritic fields stretching from spinal cord to telencephalon” (Geisler & Zahm. we must harness ethological traditions in order to better understand intrinsic capacities of organisms and thereby emphasize the importance to evolutionary constraints on learning (Tinbergen. Freeman. In addition to neural plasticity and topdown hierarchical brain processes. are needed to make sense of why organisms do what they do (Panksepp. 2005. The ARAS has also been called the “isodendridic core” of the brain. 1998. 2001). It is time to introduce such concepts into the discussion of brain DA functions since mesencephalic DA and ascending reticular activating system (ARAS) are fundamental energetic sources for many types of neural activity6 (Moruzzi & Magoun. such as instinctive and unlearned sequential grooming movements in 6The ARAS represents an endogenous system for regulating brain activity and responding to environmental stimuli and it includes interconnected neural nuclei in the brainstem. as reflected in DA facilitation of the emergence of fast-wave oscillatory rhythms in BG and cortical areas (Brown & Marsden. 1998. Panksepp. 1949. Cardinal feature of the affective neuroethological perspective Our interpretation of the behavioral functions of the ML-DA system is based on a theoretical perspective we have called the affective neuroethological view. Solms & Turnbull. We should ask why animals perceive the world as they do and are spontaneously active in globally energetic ways. 1965). Lorenz. 1965. Burkhardt. neuro-behavioral instinctual processes. 1) Energy—Modern brain research often fails to account for the energetic and dynamic aspects of neural. 2003. How can cognitive computations arise in the brain without the support of global dynamic states that channel an organism's needs via large-scale brain network functions? Where do such global states arise. the ascending DA systems forms re-entrant loops with the reticular formation. 2003). shaped by evolution.4. available in PMC 2008 December 1. Such a perspective has characteristic features that diverge from current dominant theoretical models and that focus on a series of currently neglected elements. 1998). 2001. Neurocognitive behaviorism denies (or at least ignores) an organism's intrinsic behavioral identity and thus neglects certain inborn adaptive capacities as fundamental determinants of learning (Lorenz.. Tseng et al. 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . 1949. behavioral activating properties of DA may depend on its capacity to influence global field dynamics in the forebrain.. 2003). 1981. Lindsley et al.
Housing abundant GABA inhibitory neurons. such as those used in song learning (Brainard. 3) Emotions—Dorsal BG areas control habitual behaviors.. 2005). 2000). when something perturbs its intrinsic equilibrium. Bayley et al.Alcaro et al. Page 6 rodents (Cromwell & Berridge. subcortical parts of the cerebral hemispheres (Swanson. Graybiel. extended amygdala. Heimer & Van Hoesen. 1997. particular sequences of activity are released. which are the Fixed Action Patterns (FAPs) of ethologists7 (Lorenz. especially when different sequences of actions are linked into a single functional unit (Knowlton et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 7In rodents. Graybiel. Swanson. it also helps organize a large variety of states. and associated medial diencephalic and mesencephyalic circuits. the organism's attention is focused largely on a particular set of stimuli. memories and responses. 2004. basal forebrain nuclei have been considered “doors that. such neurodynamic sequences emerge from within basal forebrain and BG areas (Knowlton et al. 1981. 1998. hypothalamic and midbrain nuclei (Kitai et a. they form reciprocal networks and send inhibitory outputs to thalamic. and nucleus of Meynert (Heimer & Van Hoesen. MacLean. 1999). 1996). which.. Jog et al. 1998. it is inadequate to try to explain motivations. as intrinsic impulses to act. Jog et al. 1996).. internal procedural drives are sequential neural activity patterns spreading within neural circuits and exerting a strong influence on brain activity.Jog et al. including BG. Brain Res Rev. BG control movements and cognitive executive processes (DeLong. Packard & Knowlton. From this perspective.. Intentions-in-action. 1999. 2006) represent the deep. 1996. Kropotov & Etlinger. Basal forebrain areas. 2000). 2003. 4) Affective feelings—Neuronal activity is not limited to the production of computational representations of the world. Such patterns represent the basic action tendencies characteristic of various primary-process emotions.Graybiel. constitute internal procedural drives8 (Llinas. available in PMC 2008 December 1. Nevertheless. the diencephalon and the brainstem. once activated. When an emotion is activated. 1996). 1990). 2002). among which the emotions and associated affects have been ignored for perhaps too long (Panksepp. 1990. For example. whose neural representations influence the activity of many different brain regions and help match perceptual and cognitive representations into a global action tendency. Behavioral plasticity arises when each emotional operating system orchestrates a wide range of potential responses in accordance with environmental conditions (Panksepp 1998). In our model. extended amygdala. Diffusion of basal forebrain/BG characteristic patterns communicates an emotional disposition within the brain. Situated between the cortex.. Berardelli et al. intentions and emotions simply from top-down cognitive or representational perspective. 1999. 2002. and septum) are involved in emotional behaviors (Koob.. whereas other basal forebrain nuclei (ventral BG. the basal forebrain is viewed as largely inhibitory with tonical suppression of behavioral actions (Swanson. 1950. Author manuscript. 2005). 1995. Llinas. 1999). In such a way. basal forebrain changes intentional states and orients behavior in specific directions. 1998. when unlocked. 1990. 1998. 2006). Gerfen & Wilson. Therefore. In primates and other mammals. may release into action large functions outside them” (Llinas. 1999). septum. Kao et al.Graybiel. while the striatum in reptiles is involved in regulation of social behaviors (Greenberg. an animal does not eat while experiencing intense fear. food is transiently excluded from its interests. and they are essential foundations for higher information processing regions of neocortex to operate.. 1998). Alheid. The homologues of BG in birds produce highly stereotyped behaviors. 8As better described in the section 4. 1951. . but one main characteristic of emotion is to regulate the organism's behavioral repertoire in flexible ways. 2003). MacLean. Emotions comprise sequences of FAPs that characterize their expressive and communicative aspects (Darwin 1872. the BG influence learning. Moreover. the BG control instinctive and unlearned sequential grooming movements (Cromwell & Berridge. Tinbergen. 1990. They push neural activity to evolve along specific directions. with parallel roles in learning and expression of motor habits and emotions (MacLean. in accordance with the sequence specified by the pattern. may best be viewed as neural dynamic sequences. 2000. especially in initiation and expression of its automatic procedural component (Graybiel. 2002).. 1996. 2002). for example..
The ML-DA system is now generally considered a key circuitry involved in promoting aroused states concerned with appetitive motivations. Moreover. Denton. and the extended amygdala (Panksepp. 1967. Porges. 1981). 1967. Olds (1977) extensively analyzed the pervasive neuronal learning during appetitive conditioning that occurred along the trans-hypothalamic self-stimulation continuum (for review. Damasio. derived from brain systems that regulate the inner states of the organisms (MacLean. However. the periaqueductal gray.. 2006). NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 2. 1999. Merker. Alheid. in part. The core affective substrate of every emotional feeling seems to be generated. Brain Res Rev. A recently re-introduced James-Lange type view of emotions considers affective feeling to be produced by “somatic marker” representations of body changes (Damasio. 1998. Chau et al. and hinder scientific understanding of how brains truly operate. 1969. Panksepp. the nature of feelings should also incorporate the intrinsic intentionality of many instinctual behaviors. increasing DA levels into the Nacc with psychostimulants enhances the rewarding properties of self-stimulation itself (Wise. gnawing and predation (Glickman & Schiff. 1998). feeding. Electrical stimulation of various brain sites in association with specific behaviors increased the probability that animals would repeat those behaviors. the hypothalamus. Craig. 2005). 2003. Bernston et al. Such stimulations also induced generalized arousal. 1998). inform hierarchically related neural networks that include.Alcaro et al. Author manuscript. 1996. Trowill et al. Damasio et al. so that the cognitive-evaluative aspects of emotion can be elaborated in a coordinated fashion by various forebrain areas. accumulating evidence for some kind of primary-process psychological experiences arising from such primitive subcortical circuits is becoming substantial (Panksepp.1. Burgdorf. 2005. an affective core underlying subjectivity appears to have emerged early in vertebrate brain evolution (Panksepp. With the characterization of brain DA circuitry (Ungerstedt.3 in Panksepp. 2007). 1996. Thus. EMPIRICAL STUDIES 2. et al. Panksepp. 1971. Sewards & Sewards.. 1996). 2003. 1971). it was suggested that ESSB foster a general incentive-based disposition to approach environmental stimuli (Glickman & Schiff. “what is going to happen” and “what may happen”. 2000). 2003. Electrical self-stimulation of the brain (ESSB) The discovery of ESSB by Olds and Milner (1954) represented a major breakthrough in understanding the neurobiological bases of reward. especially orbitofrontal and medial frontal regions. 2004) with the medial forebrain bundle (MFB) being a primary neural pathway interconnecting many relevant brain regions (see Wise 2002 for a review).. In our view. 1971. 1989 for a review). 1990.. Removing affectivity from neuroscience may lead to a profound misunderstanding of intrinsic brain organization and functioning. animals would exhibit spontaneous conditioning characteristics of fixed-interval instrumental behavior (Clark & Trowill. the core affective states are communicated to higher brain levels through the emergence of specific neurodynamic sequences. 1981. Valenstein et al. most prominently. 1981). Page 7 2005).. Schulkin et al. Such processes are not uniquely human characteristics. see Figure 8. it was further recognized that the ML-DA system is an important ascending and activating component of the MFB involved in the learning as well as in the motivational effects of electric brain stimulation (see Wise & Rompre. 1969. 2003. Further it was demonstrated that with fixed-interval stimulation of this substrate... Thompson & Swanson. 2005. attention to rewards and behavioral persistence. Panksepp. but also ”what is happening”. 2000) It was also observed that electric stimulations of the MFB not only reinforce instrumental actions.. but they also arouse a variety of consummatory behaviors such as drinking. 1971. emotions are not only a consequence of “what happened” (Damasio. 2003. leading to exploratory behaviors not strictly related to any biological needs (Gallistel. . 1974. Indeed. These studies led to the recognition of reward areas in the brain (Olds et al. 2003. 1970. available in PMC 2008 December 1. 1981). 1999). Wise. 2003.
Ikemoto et al. 2001). 2004. 1983. 1991. 2002.. 1997. conditioned approach responses (Taylors & Robbins. 1993. 1999). effects than in the Nacc (Ikemoto. 1991.. Swanson et al. Lima & Miesenbock... Microinjections of DA drugs into the Nacc increase locomotor activity and exploratory behaviors (Jackson et al. 1990). 2. DA induces hyperactivity and exploration also in adult fruit flies (McClung & Hirsh. 1993. 1997).Alcaro et al. White et al. 2004. 1997a) or NMDA agonist (Ikemoto.. 1989. the avoidance of punishement—namely the seeking of safety (Ikemoto & Panksepp.. Chase et al. and agonists of DA receptors promote waking and behavioral activation in all mammals (Randrup & Munkvad 1972.. perhaps acting peripherally (Martinez et al.. Endepols et al. et al. 1980b. Author manuscript. animals spend more time in environments associated with Nacc injections of psychostimulants and DA agonists (Carr & White.. 2005. Everitt. whereas lesions of the ML-DA system reduce or eliminate exploratory and appetitive-approach behaviors (Koob et Brain Res Rev. 2004). Psychomotor activating effects of DA drugs across vertebrates and invertebrates Drugs that enhance DA functions mediate the emergence of unconditional. 1987. 2000.g. . Bainton et al.. 1999.. Liao et al. Gong et al. 1993. Trampus et al.. 2004. 1999. Phillips et al. 2001) and DA promotes locomotor and behavioral activity in amphibians (Matsunaga et al.. Kusayama & Watanabe.. (1974). 1999. Kume et al. However. 1998). Experimental modulation of DA transmission in ventral pallidum (VP) and olfactory tubercle has similar. Hills et al.. 2003.. 1982. 1998.. Johnels. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 2. Similarly to mammals. 1998. 2005). Parkinson et al.. the rewarding properties for pro-DA drugs seem to be conserved across invertebrates (Bellen. Wisor et al. decreased DA receptor stimulation is associated with hypoactivity and catalepsy (Fog. Experimentally enhanced DA function increases behavioral activity. Mogenson et al.. suggesting a remarkable evolutionary conservation of function. 1998.. available in PMC 2008 December 1. Kelley & Delfs. Page 8 and by some.. and rodents will learn to self-administer GABA-A receptor antagonists (David et al. Animals readily self-administer DA agonists or drugs that directly increase DA transmission in the Nacc (Hoebel et al. In contrast. 1986... 2004). 1979. microinjections of various DA drugs in the VP elicit locomotion and reward-related behaviors (Gong et al. 2004) into the VTA... such as cocaine or amphetamine.... 2002. Ikemoto et al. 1997. 2005) and other invertebrate species (Torres & Horowitz. Pijnenburg et al. In fact. 2005). Nishino et al.. if high doses are used. Jorgensen. Monti et al. 2004. Wolterink et al.. 1994. 1997. Pendleton et al. Panksepp & Huber.. often even more intense. 1975. pro-DA drugs may also reduce locomotor activity in invertebrates. 1991. Stinus et al. Fletcher et al. bicuculline) into the VTA increases locomotion by disinhibiting DA neurons (Arnt & Scheel-Kruger.. 1997). 2004). Carr & White. 2001. Microinjections and lesion studies Starting with the work of Ungerstedt. Wyvell and Berridge. Burns et al. picrotoxin. Wise & Bozarth. Microinjections of GABA-A receptor antagonists (e. 1982). 1998) whereas VP lesions reduce responses to natural and artificial rewards (Hiroi & White. Carlezon et al. Panksepp & Huber. Ikemoto et al.. Wolf. Sawin et al. 1998). 1990).. they show stereotypical behaviors (Wise & Bozarth. 2000). Pavlova. pharmacological and lesion studies of areas with ML system cell bodies (VTA) and projections have clarified the behavioral functions of the DA transmission in mammals. 1995. injection of cocaine increase locomotion in birds (Levens & Akins. 2000. 1972. In the conditioned place preference (CPP) paradigm. 2000. 1987).. Rats and mice increase locomotor activity in response to such drugs and... behaviorally aroused state in many species. 1988.3. 1986. Reyes et al. Although effects of DA on invertebrate locomotion are not uniform.2.. Facilitators of DA release. 1976. and anticipatory sexual behaviors (Everitt et al. Brembs et al. Schildein et al. 1996. 1998. DA enhancing microinjections are also associated with rewarding properties.
A significant negative correlation also exists between mesocortical DA transmission and locomotor activity (Hedou et al. 1996). inhibition of DA transmission within the amygdala reduces fear-potentiated startle (Greba & Kokkinidis. Hemby et al.. Park et al. On the other hand. . 1980.. Schildein et al. 2005)... 1999). Koob et al. 1978.. both positive and negative emotional behavioral dispositions appear to be stimulated by DA in the amygdala. Andrzejewski et al. 1999... 1993) or self-administration of intravenous cocaine (Martin-Iverson et al.. microinjections of DA agonists in the pFC decrease spontaneous. ML-DA transmission within the amygdala (in basolateral as well as in medial and central nuclei) has been implicated in the expression and learning of fear (Pezze & Feldom. McGregor et al. McCullogh et al. 1978) and have anti-depressive effects9 (Espejo & Minano.. 1999). 1986. Whereas rats self-administer cocaine directly into pFC and cocaine injected in the medial pFC induces CPP (Hemby et al. 1986. Pfaus & Phillips. On the other hands. 1987. 2004. 2005). even though not to the point of affective neutrality. Jones & Robbins. while DA transmission in the basolateral amygdala contribute to the establishment and reinstatement of instrumental and associative reward learning (Zarrindast et al. 2003. On one hand. Much more work is needed on such aversion related affective issues..... 1999). 1991. 1996.Alcaro et al.. Robbins et al. Schenk et al.. 2000). Taghzouti. 1992. Beyer & Steketee. available in PMC 2008 December 1. We would argue that in the absence of negative incentive stimuli. Lacroix et al. However.. 2004). we do not know whether this contribution is to directly facilitate aversive feelings or alternatively. Pharmacological reduction of Nacc DA transmission inhibits seekingapproach behaviors in response to reward-associated cues (Blackburn et al. Ventura et al.. 1985. Pierce et al. 1991. In contrast to the role of DA in ventral BG and prefrontal areas.. pFC DA lesions produce hyperactivity (Tassin et al. 2001). Interestingly. 1992. 1984. 2000. intra-medial pFC injections of amphetamine produce moderate increases in open-field activity (Carr & White. 1977. 2005. Liu et al. Alleweireldt et al. Author manuscript.. the retrieval of conditioned-fear associations (Nader & LeDoux. and has a general anxiolytic effect (de la Mora et al.. 1999. the ML-DA system largely promotes positive affective states. Kelley et al. Broersen et al.. The functions of DA projections to the pFC are less clear.. 1993). suggesting that ML-DA also participates in the seeking of safety (Ikemoto & Panksepp. 2002. 2002. since DA elicits active but not passive avoidance behaviors... Parkinson et al. Fink & Smith. 1998). 2002).. 1993. Wakabayashi et al. 1989... Burns et al.. 2002). It has also been shown that lesion of mesocortical projections do not reduce reward learning (Isaac et al. Di Ciano et al. leading to heightened levels of emotional acting out (Panksepp. Page 9 al. McFarland et al. Sun & Rebec. the frontal cortex control and inhibit primary-process emotional processes such as those that may be disinhibited in attention deficit. 1985. Additional dilemmas exist concerning the role of mesocortical DA transmission in mediation of reward. 2006)... 1990). Evenden & Carli. Consistent with these findings. 1998). 1989) and DA transmission in the pFC is involved in the reinstatement of cocaine seeking-behaviors in rats (McFarland & Kalivas. amphetamine in the medial pFC is not self-administrated (Goeders et al. 1986) nor does it induce CPP (Carr & White. 1982. 1990.and psychostimulants-induced locomotor activity (Radcliffe & Erwin. hyperactivity disorders (ADHD). 1998). NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 9In our opinion. it may be argued that central amygdaloid DA is still involved in promoting energized “approach towards safety” (Ikemoto & Panksepp. 2001. 2004). rats self-administer damphetamine directly in the central nucleus of the amygdala (Chevrette et al.. For example. 2001. 1989. and that only in the presence of various concurrent negative emotional states or stimuli might it contribute to aversive feelings. However.. 2000).. In sum. 1992. perhaps to dampen those feelings. Brain Res Rev. Shippenberg et al. Robbins & Everitt. ML-DA depletion or inhibition disrupts active-avoidance behaviors (Jackson et al. novelty.
1999) and novel stimuli or environments (Rebec et al.. However.. et al. 1997. Hedou et al. 1997). 2001). the establishment of Pavlovian or instrumental conditioning (Parkinson et al..4. 2002). 2005). 2006). Besides the neurochemical differences between the core and the shell of the Nacc. Parkinson et al. 1999)... the DA transmission in the core may be involved in the expression of this emotion in the BG-thalamocortical circuits and then in the “control of goal-directed behavior by associative process” (Ito et al. Ikemoto. On the other hand. Barrot et al. Ikemoto. 1999. nonsynaptic (Vizi. West et al. Zahm. conditioned reinforcement (Parkinson et al. Ikemoto et al. 1996). Conversely. the density of [3H]mazindol binding sites in the Nacc was examined by autoradiography and the shell was found to have an average of half the number of DA uptake sites than those measured in the core region (Jones et al. 1996. The Nacc core/shell distinction The Nacc consists of two anatomical and functional subdivisions. 1999). 2003) or volume transmission (Sykova. 2004). the shell and core (Zahm & Brog. However. Horger et al. ventral shell and lateral tubercle (Ikemoto et al. It has also been shown that rats learn to self-administer the psychostimulant in the medial shell and in the medial tubercle. Indeed. available in PMC 2008 December 1. 1992. the amount of extracellular DA could be greater in the core due to a faster rate of release and uptake. 2002.. 1992). Boye et al. 1999.. Ito et al. Sellings & Clarke. Chevrette et al. in the shell (Heidbreder & Feldon. King et al.. Sellings & Clarke.. 1998. 1999... and in both structures (Pierce & Kalivas. 1995). including drugs of abuse (Pontieri et al. 1995. support instrumental behaviors and CPP (Carlezon & Wise. 2003). 1992. Together.. 2004. but not the core. 1997. In fact. important functional differences appear to be associated with these subregions. 1996. 1997. It is generally accepted that the shell is involved in mediating the rewarding effects of psychostimulants (Parkinson et al. studies in postmortem tissue punches revealed that basal DA levels are greater in the shell than the core. DA transmission in the shell of the Nacc has different characteristics when compared with the transmission in the core. For example. 1999. 1999. Page 10 2. 2000). 2001. Heimer et al. food. 2000). RoddHenricks et al. while rewarding effects of the psychostimulant depend upon DA transmission in the shell and into the olfactory tubercle (Sellings et al. 2004).. while the DOPAC/DA ratio is greater in core (Deutch & Cameron. Ito et al. Basal extracellular DA levels are greater in the core and ventral medial pFC than the shell (King & Finlay. 1999.... 2002. while the locomotor activating effects are mediated by the Nacc core.. Kalivas & Duffy.. 2005). 2003). excitotoxic lesions of Nacc core disrupt Pavlovian approach behavior (Parkinson et al. Author manuscript. Di Chiara. DA projections to the shell are more sensitive to a great variety of stimuli.... 1995. 2001. previous findings demonstrated that DA transmission in the core is necessary for some associative processes. Hutcheson et al. (Bassareo & Di Chiara. Di Ciano et al. The DA volume transmission in the shell of the Nacc may be involved in the generation and the maintenance of an aroused and positive affective state.Alcaro et al. restraint and pharmacological stress (Deutch & Cameron. Moreover. 1995... but not in the core. in vitro voltammetric studies show that the values of DA release and uptake in the shell Nacc are approximately one-third of those measured in the core region. Although these findings indicate that rewarding effects of psychostimulants are mediated by Nacc shell and olfactory tubercle. 1999) and Pavlovian to instrumental NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev. these findings suggest that DA transmission in the shell of the Nacc presents the characteristic of so-called slow (Greengard et al. DA transmission in the core seems to be more confined to the synaptic clefts. Rebec. the behavioral activating property has been attributed to an action of psychostimulants in the core (Weiner et al. Moreover... 2006). 2002. Interestingly.. but there is less agreement concerning the psychomotor activating effects of these drugs. Bach-Y-Rita. Hall et al.. 2004). for instance. 2000. microinjections of DA drugs into the medial shell. 2001.. a recent experiment indicated that the locomotor activating properties of cocaine depend upon DA transmission into the core. 1997. Kelley. Although the total amount of DA (extracellular + intracellular) could be higher in the shell. . 1998..
. 2002). Hyland et al. tonic DA activity may block the cortical and limbic top-down control.5.. or when organisms are actively engaged with the environment (Thierry et al. 2003. 2003.. available in PMC 2008 December 1. 1981... 2000.. 1996. 3A) (Grace.Alcaro et al. 2001). Electric activity of DA cells: phasic and tonic DA transmission Phasic DA transmission is the short-lasting and impulse-dependent release that appears as a consequence of neural burst firing (Gonon. novel and rewarding stimuli induce transient DA cell bursts (Miller et al. Solms.. 1993. However.. and acts as a detector of coincidence when coupled with glutamatergic inputs directed into the Nacc (O'Donnell. increased amounts of tonic extracellular DA levels exist during emotional arousal... However. 1985) and microdialysis (Smith et al. 1988.. 1981.Schmitz et al. either in aversive and appetitive conditions. Self. Dalley et al. since DA neurons do not alter firing rates with waking and sleep (Trulson et al. Schultz et al. Activating the D2-type inhibitory postsynaptic and presynaptic receptors. 2005). 4). Miller et al. phasic DA may promote not only reward-related learning (Reynolds et al. Page 11 transfer (Hall et al. at least partially. It has recently been proposed that phasic DA in the Nacc is the key component in the process of reward (Grace. 2005). Roth et al. . Freeman et al. Effects of stress on DA cell bursting is also not clear with some reports of a reduction in bursts or no effect (Ungless. and change relatively slowly (Grace.and space-specific event. and there is also enhanced release during REM-dream episodes (Miller et al. 2. 1997. Cooper. by transient DA release (Wise.. 2003. 2003) and that the rewarding effect of electrical stimulation of the MFB is mediated. 1999). 2003. Evidence from voltammetry (Trulson et al. 1983. Horvitz et al. Author manuscript. Suaud-Chagny et al. while coincident activations of D1 receptors and NMDA receptors in the Nacc core are necessary for associative learning (Smith-Roe et al.. 1994). necessary for associative learning. 2006)... To the contrary.. 2002). Cousins et al. 2005). 2004). Wickens et al.. 1984.. 1992)... 2005). The presence of unpredicted salient. 2004).. 2001) but also motivated behaviors (Phillips et al. 2000. 1997. Feenstra et al. Following such bursts. and then rapidly removed via a re-uptake system (Floresco et al. Lena et al. 2000. tonic DA generally reduces the influence that descending glutamatergic projections exert over neurons in the BG and VTA (Nicola et al. 2000.. Since DA is transiently released before the execution of goal-directed movements (Phillips et al. 2000. 2003). Maloney et al. 2002. with increases in burst firing observed by others (Anstrom & Woodward. Steinels et al. 2002. 2003).. In such a way. Gottesman. 2005) illustrates that tonic DA is sensitive to fluctuations in sleep-wake states. 2000.. Roitman et al. 2003).. 1976. The role of phasic DA in reward processes is envisioned to reflect the fact that phasic DA is a time. Schultz et al. Wightman & Robinson. 1988. 2000. 2004... Schultz. Horvitz et al. long-lasting elevations of tonic DA levels may also NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev. 1999. 2000). Mirenowicz & Schultz. Hernandez et al. 2002).. Trulson & Preussler. It has been demonstrated that tonic DA reduces the firing of DA neurons and phasic DA release via D2 autoreceptor activation in terminal projections and soma (Fig. 1993.. suggesting a role of phasic DA in the salience attribution process or the attentional-exploratory behavior that always follows such waking events. Ghitza et al. Schmitz et al. Di Chiara et al. 1983.. 1983. tonic DA levels are diffused in the extracellular space outside the synaptic clefts... high levels of DA molecules are released into the synaptic cleft at up to mM concentration (Garris et al.. 1998. favoring the expression of behaviorally aroused states generated subcortically (see Sect. the overall mean DA cell bursting (and firing) appear independent from the tonic arousal state of the organism... 1992. In contrast. but exist in very small concentrations (in the nM range). 1985. Steinfels et al. 1983.
2004). 3B). Wickens et al. but reduce the excitability of DA cells to descending excitatory glutamatergic inputs. potentiating the effect that each impulse will produce in term of extracellular DA release. the impulse-dependent DA release may arise from an increased amount of molecules released per impulse. 3. Brain Res Rev. In particular. 1996). Psychostimulants increase tonic DA levels into the Nacc.. can be conceptualized as computations for unconscious control of behavior and modeled in accordance with information processing theories (Kihlstrom. 2002. 3). 2004). Two lines of evidence suggests this hypothesis: 1. Martin & Levey... behavioral and psychological levels guarantee the presence of substantial gaps in our understanding that remain to be filled. a less excitable system may be characterized by the fact that each action potential now has a greater power of each impulse. amphetamine produces an impulse-dependent DA release into the Nacc (Ventura et al.. Continuous electrical stimulations of DA cells progressively decrease impulsereleased DA quanta (Garris et al. 2001. 1913. Vogel. 1987). Nestler. The adoption of novel integrative hypotheses may be essential for promoting empirical predictions that can help fill the remaining gaps. 1999). by presumably potentiating the amount of phasic DA released after each stimulation. Moreover. (2) Cognitive processes. Within this context. acting either indirectly via D2 receptors located on DA neurons or directly on glutamatergic terminals reaching the VTA. Reynolds et al. 2001. which may be associated with its rewarding effect. 2004. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 2. (1) Animal (and human) behaviors are the product of associative memories stored in the brain (Watson. In conclusion. Hyman & Malenka. Since amphetamine generally suppresses the electrical activity of DA neurons (Westerink et al. It is characterized by two main assumptions. we are tempted to hypothesize that high tonic DA levels will predispose to a less excitable but more powerful ML-DA network influences.. available in PMC 2008 December 1. 2003. Skinner. we suggest that high levels of tonic DA do not decrease the total amount of phasic DA per se.. Neurocognitive behaviorism Much of today's experimental work is driven by a common theoretical perspective.. and thereby enhance the rewarding properties of self-stimulation (Wise. . Gerstner et al. 2001. although the inhibitory action of tonic DA over phasic DA has been emphasized (Grace.. 2001a. Miyashita. 1996b. 2005). Resler. 1999. 2004. 1999. Fuster.. the possibility of positive reciprocal feedbacks should also been considered (Fig. THEORETICAL INTERPRETATIONS Complex relationships among neural. 2000). 3.Alcaro et al. Behavioristic and cognitive approaches have melded together since associative learning is considered the process through which organisms acquire and modify their predictive cognitions (Sutton & Barto 1981). Ventura & Puglisi-Allegra. 2004. 1988. investigators need to consider that if an electrically overactive system promotes blunted phasic DA release. Therefore. enhanced synaptic plasticity (Centonze et al. 2003). Considering the motivational properties of ML-DA transmission.. Author manuscript. here termed “neurocognitive behaviorism”. 2004). 2002. Therefore.. 1938. 2003. 1997. mediated by higher cortical functions. 2004. 2005). and facilitated neural communication (White. Barrot et al. high levels of tonic DA will increase the quanta of DA released per single impulse. Robinson & Kolb. Page 12 increase the quanta of DA molecules released per single burst (Fig. 1987. However. Huang et al. Centonze et al. Li et al..1. Nestler. the principal focus of research is to clarify how DA modulates learning by sustained alterations of intracellular molecular mechanisms (Greengard et al. Rolls. Pickens & Holland.
2000).. 1981). 2004. is viewed as a product of abnormal learning. 1999. view learned behavior as the product of anticipatory expectations processed within the brain.. TD models describe “the function of reward according to the behavior elicited. 1987) the generation of positive affective states (Drevets et al. Dayan & Balleine. Cooper. 1999. If addiction is a learned process. 2002. 1997). Murer et al. It is also unresolved why individuals show differences in dispositional vulnerability toward addiction (True et al. 2004.. it remains difficult for such models to explain how increased ML-DA transmission also promotes certain kinds of unconditional responses. 2001. appetitive or rewarding stimuli induce approach behavior that permits an animal to consume” (Schultz et al. Carelli. Formal models of DA functioning Electrophysiological recordings from DA neurons generally demonstrate that these cells burst when a reward value is better than expected (Schultz. and then manages information flow from cognitive representations (neocortical and higher limbic areas) to movements (BG areas) (Cepeda et al. Waelti et al. Ungless. 2003. 2004). Self. 2002. 2000.. Drug abuse. Waelti et al. TD models. Wightman & Robinson.. 2002). whose rewarding value is measured by how strongly it entices the organism to approach or proceed with a sequence of learned configurations. 2002.. Page 13 neurocognitive behaviorism is characterized by a top-down. 1981.Alcaro et al. 2000. 2004). West et al. Joel et al. For example.. 2003.. 2000. Burgdorf & Panksepp.. Dayan & Balleine. available in PMC 2008 December 1. 1999. for example. occurring when the associations between external predictors of the drug's presence and behaviors directed towards its acquisition and consumption progressively consolidate (Robbins & Everitt. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . Montague et al. Kelley. such as behavioral activation expressed in exploratory-investigatory behaviors (Panksepp. Despite such theoretical successes. Di Chiara et al. Motivations are viewed as cognitive representations of future goals elaborated in cortical structures. Wolf. 2006). DA transmission is thereby conceptualized as a teaching signal.. Author manuscript. 1999. and that animals tend to seek out those that offer the greatest reward. 5). 2002.. The neurocognitive behaviorist perspective has advanced hypotheses about the etiology of DArelated psychiatric diseases. Schultz & Dickinson. Phasic (or transient) DA transmission is thus viewed as key for organisms to change their internal cognitive schemata in relation to what happened around them (Grace. 2001. In the establishment of compulsive seeking behaviors. 1997. Uhl. Schultz & Dickinson. Robinson & Berridge. Berke & Hyman. incentive salience orientation of brain functioning rather than a bottom-up view that envisions brain DA to facilitate ingrained psychobehavioral subroutines necessary for survival. 1999. which reorganizes cognitive representations by indicating prediction errors (Redgrave et al. O'Donnell. Everitt et al. 2000). 2002. 1998. Reynolds et al. A core problem of TD models Brain Res Rev. 1997. Di Chiara. 2000) (see Sect. Wise & Bozarth. Nicola et al. These expectations are modeled in algorithmic computations capable of predicting the reward value of stimuli which are dynamically modified by experience. 2002. 2001b. 1981). Kalivas & Nakamura. 2004). Nestler. just like some ethological models (Panksepp.. 2001. which thereby control the activities of motor circuitries. the critical step is the cortico-striatal circuits fueling by druginduced DA release (Pierce & Kalivas. 1998. 2001. what predisposes an individual to be a good or bad learner? 3. Only recently. 2000. DA regulates the communication between cortico-limbic inputs and Nacc neurons. Such formal models predict that each collection of sensory cues represents a specific reward value. 1999. The new data on DA transmission seem congruent with temporal difference (TD) models for reward learning in animals (Sutton & Barto.. have such models been utilized to explain DA functions within the brain (Schultz et al. A movement may be defined as activity leading to a sequence of perceptual configurations. 2004).2. 1997. Vanyukov & Tarter. Within this worldview. 2002. 2001.
initial presentations of reward-predicting stimuli transiently stimulate the DA system. In such cases. Blocking DA activity in the Nacc strongly diminishes maze-running speed. . Reduced DA activity diminishes the appetitive urge more than consummatory pleasure10. past experiences determine the succession of perceptual configurations embedding them within the organism motor-cognitive habits. In other words. where no reward value has been solidified by previous learning. 1981. 1978). Thus incentive salience may be as much a reflection of changing action readiness as any changing properties of the perceptual field. and phasic DA transmission activates the sequences leading to the predicted outcome. 2003) may promote the emergence of an unstable state. These problems may be well addressed by considering that sensorial configurations are embedded into pre-motor sequences leading organisms to move within and between these configurations. a series of configurations is evoked by previously acquired knowledge so the SEEKING urge is manifested in the tendency to run along the entire sequence until the final configuration is reached. In learned situations. which is essential for associating sensory cues with future rewards along a number of intermediate time points.. 1989 for a review) led to a provocative and for a while seminal hypothesis to explain both motivational and learning effects of the ESSB (Wise et al. ML-DA thus appears more concerned with “wanting” and less with “liking” (Berridge & Robinson. even though consumation of available rewards is unaffected (Ikemoto & Panksepp. all emotional systems control sensory input gating. Page 14 concerns a stimulus' temporal representation (Schultz et al. those animals exhibit more directed appetitive behavior toward stimuli associated with rewards in the past (Wywell & Berridge. In our view. The persistent increase of DA cell firing in such unpredictable conditions (Fiorillo et al. by facilitating arousal of this system with amphetamine in instrumentally conditioned rats. in such formal models. formal neurocognitive behaviorist models of DA functions are built upon a disconnection between brain information-processing modules responsible for the cognitive prediction of reward and those intrinsic brain circuits responsible for the natural behavioral patterns exhibited during reward seeking. 1989. Author manuscript. It is possible that the neural circuitry that subsumes the SEEKING response is the only “ground state” in the brain upon which effective information processing can proceed. This idea is consistent with evidence from pharmacological manipulations of the ML-DA system in the context of instrumental behaviors. the reward value of a stimulus is the product of the sustained emotional tendency to unconditionally move towards certain objects within the environment. 1996). how a representation of reward value is translated into concrete actions and how the animal behaves in novel situations. In well-learned situations. 1998). in novel situations (or when the reward delivery is maximally uncertain). 1982. Likewise.Alcaro et al. In novel and unpredictable contexts. Criticism of the hedonic hypothesis emerged from the demonstration that more intense activation of ML-DA occurs during the appetitive phase. these two aspects are part of the same integrated process: an intrinsic instinctual action tendency to move across perceptual/cognitive landscapes so as to approach towards specific outcomes within environments. on the other hand. characterized by the release of instinctual behavioral arousal patterns. than during the consummatory phase of motivated behaviors (Blackburn et al. 1998). which drive organism to explore external stimuli and to cope with life-challenging events in unpredictable environments (Panksepp. Yet it remains unclear. 2001).. The incentive salience hypothesis Recognition of a direct involvement of the ML-DA system in the behavioral effects of ESSB (see Wise & Rompre. as well as selective responses to those stimuli. available in PMC 2008 December 1.3. Panksepp. 1986). fixed sequences of movements across sensorial configurations have not yet been established. 2000. 1997). In sum. 1981a. However. 3. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev. Stimulation of the ML-DA system induced a positive hedonic state and enhanced the pleasure derived from consummatory behaviors. 1987.
. “when incentive salience is attributed to a stimulus representation. Indeed. it is unclear why animals would seek to self-activate their own general purpose. appetitive states. 1996. while a recent study demonstrated that strongly valenced tastes. Thus. This disposition consists of instinctual behavioral tendencies that help organism to move accross sensorial configurations and to approach specific sources of stimulations. In this “active-organism” view. including salient non-reward events (Horvitz. 1989. Ragnauth et al.2005). both pleasant and unpleasant. Kelley & Berridge. it makes the stimulus attractive [and] attention grabbing” (Berridge. may promote DA arousal (Roitman. Focusing on this aspect. initially objectless. such a behavioristic shift of focus from the organism to the environment can be misleading. rather than from internal drives. Since animals self-stimulate the ML system. an intrinsic psychobehavioral function of the brain. 1998. 1998). Hoebel et al. DA is a promoter of the motivational salience of external stimuli. without implying any conscious experience of affective quality. an internally generated action tendency (i. in our estimation. Author manuscript. Spence. Martel & Fantino. 2004 for a review). ML-DA transmission subcortically promotes the emergence of the emotional SEEKING disposition. 1998). many experiments have pointed to the involvement of ML-DA transmission in the consummatory phase of motivated behaviors. that evolved to cope with all varieties of life-challenging events in unpredictable environments (Panksepp. 1943. Moreover. Brain Res Rev. Since ML-DA transmission presumably helps an external stimulus to acquire incentive salience (Berridge & Robinson. 195). As a solution to the dilemma. 1960). Berridge claims that motivations are commonly activated by the presence (or anticipatory representation) of external stimuli and not necessarily by internal drives nor affective states. and partially controls food intake (Hernandez & Hoebel. 1981. Although the role of external stimuli for guiding motivational processes are undeniable. in drive-reduction theories. 2005). Page 15 According to Berridge. Berridge's perspective attempted to explain the role of DA transmission in the absence of any pleasure (specifically sensory “liking”). every consummatory behavior also has an appetitive component (animals fluctuate between approaching/manipulating and consuming the food). “Liking” has been considered independent from DA transmission.4.. only the reduction of a drive was originally related to the reward.e. Nevertheless. Indeed. 1972. 2004 p. which is strongly controlled by brain DA availability. Therefore. However.Alcaro et al. Bindra. Otherwise... that acknowledges the existence of experienced affect. Mowrer. MacDonald et al. Berridge proposed that appetitive behaviors arise from the attribution of incentive properties to external stimuli (pursuant to the views of Bolles. The SEEKING 10Nevertheless. 1974. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . Berridge (2004) concluded that problems in the field arise when we wrongly believe that appetitive behaviors are direct expressions of what used to be called “drives”. the SEEKING instinct) lies at the very center of information processing.. it needs also to be explained why the activation of an appetitive “wanting” state has its own rewarding properties despite being considered an unconscious process. 1956. such as feeding (see MacDonald et al. The affective neuroethological perspective With a focus on the unconscious attributions of salience to external representations. 2000). 3. the manner in which ML-DA transmission may increase the incentive salience of external stimuli is by changing the self-referential attitude of the organism towards those stimuli. and hence it is not surprising that DA transmission is enhanced during feeding. Toates. it is important to emphasize that taste pleasure may not exhaust the range of possible positive affects that may be facilitated by brain DA arousal. while the drive itself was deemed to be aversive (Hull. et al. appetitive motivation as a real process within organisms. 2000. available in PMC 2008 December 1. as DA does not seem to promote hedonic taste reactions (Berridge & Robinson. 2002. it also influences the learning of stimulus-related contingencies and appetitive motivations to approach the stimulus. 2004). 1988. 1986).. an excessive reliance on how perceptual stimuli guide behavior could obscure an intrinsic.
sniffing. 2005).. both through attentive processes as well as favoring the recollection of past events related to the arousal of the SEEKING state. Moreover.. Author manuscript. independent of world events. available in PMC 2008 December 1. Indeed. a DA energized response. et al. 2002. Moreover.Panksepp. Similarly. “interest”. et al.Romach. Brain Res Rev. this phenomenon is also evident in 50 kHz chirping of rats (Burgdorf et al. investigating. 1981a).Alcaro et al. In these two cases. medial frontal cortex). fixed-interval delivery of rewards (Clark & Trowill. 1998. 2003). The SEEKING disposition may be viewed as an affect-centered instinctual structure binding together perceptual and motor configurations. 1994. the SEEKING disposition. that neutral cues initially provoke sniffing. 11This does not mean that DA arousal might not contribute to coping with aversive situations. it has been demonstrated that operant responses for electrical brain stimulation are always preceded by some exploratory or investigative behaviors (Ikemoto & Panksepp. In classical conditioning. 2006). 2003. et al.and cuepredictability of rewards. 1997. It is well-established that emotions affect memory consolidation and retrieval (Cahil. 1996). 1981. manifested at the cortical level (e.g. Wise. even though it may not eliminate them.. ML-DA transmission may then facilitate learning. promoting the urge to project oneself forewaord in space and time. solidifies the previously related appetitive activity. Page 16 disposition is manifested in energized behaviors such as forward locomotion. 2000.Burgdorf & Panksepp. Unconditioned rewards may thus promote associative learning to the degree the SEEKING disposition has been aroused. 2005). it is very probable that associations have been established between the SEEKING disposition and the operant responses. By promoting the expression of the SEEKING disposition. not the “pleasure of satisfaction”... 2006). On the other hand.Newton. The activation of the emotional SEEKING disposition by particular environmental stimuli facilitates instrumental responding within other contexts. For example. would also have its own hedonic properties. In such a way. 1971. and ultrasonic 50-KHz vocalizations in rats (Ikemoto & Panksepp. and “euphoria”11 (for relevant subjective human data. an unconditioned component of ML-DA network activity (Burgdorf & Panksepp.. orienting movements.. positive expectancies and anticipatory states (Panksepp. Such an automatic. Additional evidence supports our view. associative process relates to temporal. 2005). so they are released whenever the SEEKING state is again activated (independently of the stimuli that were originally involved in the generation of that state).Volkow & Swanson. 2001. Roozendaal et al. but “enthusiastic positive excitement”. It is noteworthy. an environment associated with food delivery enhances the locomotor activating effects of amphetamine as well as an environment associated with the amphetamine (Yetnikoff & Arvantogiannis. McGaugh. but this effect habituates rapidly (Clark. diminished foraging) or perhaps those associated with the pleasurable interaction with the reward. when the reward arrives and animals begin to exhibit consummatory behavior. Panksepp. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . 2001. 2000). The role of the SEEKING disposition in learning is evident in the shaping of spontaneous sniffing behavior in rats during the free. the presentation of a conditioned stimulus enhances instrumental response also for unconditioned stimuli different from the one the conditioned stimulus had previously been paired with (Corbit & Balleine. 1971. 2004). 1999. Richter-Levin. the changing neurodynamic of the SEEKING state (e. The SEEKING disposition. we would simply predict that it generally tends to counteract negative feelings.. 2001. 1972). Panksepp & Trowill.Jönsson. “desire”. see Drevets et al. Bernston et al. Packard & Cahill. 2001.g. 1970). novel or unusual stimuli can be associated with unconditioned stimuli whereas habitual stimuli in familiar environments do not condition readily (Rescorla & Wagner. may facilitate the generation of higher-order “forethought”.. associations between perceptual and motor representations may follow the connections that each of them has established with the SEEKING state. the effects of the stimulus (or the environment) on the animal's performance cannot be explained by direct stimulus-response associations simply because these associations have never occurred. Moreover.
Yang & Mogenson. 1998. Nieoullon. DA projections to pFC may facilitate information processing without activating the affective-emotional. to BGthalamocortical circuits via midbrain DA neurons. 1990. Castner et al.. and leads to permanent synaptic changes (Greengard. In contrast.. Harvey & Lacey. It has been argued that behavioral arousal emerges from a DA disinhibitory role obtained by the block of an inhibitory pathway. this proposal needs an elucidation of the role of DA in modulating neural activity across brain circuitries. NEW INROADS OF THE AFFECTIVE NEUROETHOLOGICAL PERSPECTIVE In the previous section. 1990. 1997. Wilkinson. 2003). the affective neuroethological perspective of the ML-DA system is centered on the SEEKING disposition concept. 1985. should be integrated with neurophysiological findings about the effects of DA in its projections areas (which better informs us about what DA doing as it is being released downstream of the inputs). Peoples & West.. 1996. Along with many other G-protein–coupled receptors (Hille. 2002). Greengard et al. Yim & Mogenson. 1996. 2001. Hu et al. 1989. Nisenbaum et al. 1986. DA modulation of neural activity Binding to its receptors. the two main BG output nuclei (Alexander et al. Rowlands & Roberts. It is now important to provide new hypotheses describing how this disposition is processed in the brain. it is also likely that DA-promoted pFC functions may hinder the overt expression of the SEEKING disposition in such highly aroused situations. Zhang et al.. Schultz and colleagues. 1997. 4. and influences behavioral processes by modulating large scale neural activity in widespread neural networks. 2004.. 2003. 1986... In our view. 2000) and communicated.. Parvizi & Damasio. 2000. Nicola & Deadwyler. 1999). as is common in the otherwise excellent electrophysiology work of W.. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 4.. Pennartz et al. in part. the attentive and executive functions controlled by mesocortical DA projections (Goldman-Rakic et al.. 1998. DA receptors alter neuronal excitability via modulation of voltage-dependent ion channels. and may potentially inhibit positive affective states. 2001. . DA activates a cascade of intracellular processes with many diverse neural influences (Missale et al. Jentsh et al.. 2004). 1983. 1992. Since under stressful conditions DA transmission in the pFC inhibits DA release in the Nacc (Deutch et al. Nicola et al. DA transmission also regulates gene expression. Page 17 In sum.. euphoric aspects of the SEEKING urge. Dray. 1996. 2002). 1982. Brown & Arbuthnott. including variants of enhanced incentive salience and the maintenance of effortful behaviors (Salmone. 1988. DA release generally depresses spontaneous and evoked cell firing (Siggins. 1996. available in PMC 2008 December 1. Hu & Wang. 1997. Peoples et al. we described how the behavioral functions of ML-DA emerge from its ability to activate the SEEKING emotional disposition. see Panksepp. 2005). from changing the activity of ion-channels to altering the functionality of different membrane receptors. Arnsten & Li. et al. Damasio. 1983. Indeed. 1990. ventral BG-DA transmission is essential to the behavioral and mental expression of the SEEKING disposition. Ventura et al. the main targets of DA neurons are BG GABA inhibitory neurons (Graybiel. 1984. 1998. 1980. Such perspective can easily incorporate most of the other views.. Wolf et al. 2005).. but not necessarily what message they are passing on. Gerfen et al. Johnson et al. 1980. 1986. 2005) may constitute more sophisticated cognitive processes related to the SEEKING disposition. Nestler. Author manuscript. 2000. Bergman et Brain Res Rev.. whose ability to explain both motivational and rewarding function of DA transmission is unique among existing scientific scenarios. 1978.1.. Karreman & Moghaddam. King et al. Indeed. Albin et al. 2000. 1994). Chiodo & Berger. 2002. 1988.. and DA decreases firing in the globus pallidus and the substantia nigra.Alcaro et al. correlative neurophysiological observations obtained from recording DA neurons (which tell us much about what DA cells are listening to. Groenewegen. The core of the SEEKING affective state may be generated in midbrain and hypothalamic areas (Panksepp 1998. DeFrance et al. Obviously. As many empirical findings demonstrated (see section 2).
2002. in a manner similar to NE. 1996.Bandyopadhyay et al. 2001). Brown et al. O'Donnell 2003). Gerfen. Based on information from large-scale populations of neurons.Hu & White. 1994.. an alternative picture is now emerging. 2005)..West & Grace. Priori et al. 1996. 2000.. DA also enhances spontaneous and evoked neural activity in striatal as well in cortical neurons12 (Gonon & Sundrstom. 2002. available in PMC 2008 December 1. 1996. Reynolds et al. blocking the spread of cortical synchronous oscillations into the BG (Marsden et al. 1985. 1998. Floresco et al. The general interpretation of such bidirectional effects is that DA. 2000.Chen et al. 2002).. Hernandez-Lopez et al. 2000). b...O'Donnell & Grace. 1995. 1997... Chao et al.Pennartz et al. West & Grace. 2002. 2002. 2003. and translating motivational representations into executive motor plans (Mogenson et al. 1980a. 2000. 1998. 1994. 2000. Nini et al.. favoring the entrance of salient signals in BG-thalamocortical executive circuits (Mogenson et al. Page 18 al.. It also promotes a greater autonomy of BG neural patterns from a strict cortical control. while facilitating and enhancing neural activities related to significant incoming signals (Rolls et al.West & Grace.. 2004). Hutchison et al. 1998... 2003) and gates information to the Nacc. while D1-type receptors feature both excitatory and inhibitory roles (Hernandez-Lopez et al.. top-down perspectives of ML-DA system are largely built on the observation of DA effects on single neuron firing (Schultz.. 1997) while higher concentrations inhibit firing rates (Williams & Millar.Charara & Grace.2.. and excites depolarized ones (up-state) (Cepeda et al. Williams et al.Gonon. 1997. and amygdala (Pennartz et al. 2001.French & Totterdell. 1998. Lee et al. 1990). ML-DA also strengthens synaptic associations between descending glutamatergic projections and BG neural ensembles. 2002. 2002. 2004)... 2002. 1980a. Goldberg et al. 2004.. 1997. DA may filter spurious activity and suppress background noise. Brown. 2001a. hippocampus. 2003). Cassidy et al.Alcaro et al. 2002)..Nicola et al. 1996.Brady & O'Donnell.. 2002. 2004. 4. 2004. Brown.. Nicola et al. Vitek & Giroux. 2003. 2001.. 1997. 1999. 1984.Cepeda et al. 1994.Redgrave et al. 2004)... Sharott et al. (2) Steady-state membrane potentials: DA inhibits hyperpolarized neurons (down-state). Brown & Marsden. DA then modulates synaptic communication (West et al..O'Donnell. 2001. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Despite a predominantly inhibitory role.. Wilner & Sheel-Kruger. Kiyatkin & Rebec. 2005) (Fig. 1991. 12The impact of DA transmission on neural activity seems to depend on three main factors: (1) DA receptors: D2-type receptors are inhibitory.West et al. 1995.. that receive multiple converging inputs from pFC. 4A).. Heimer et al.O'Donnell & Grace. DA decreases the power and coherence of cortically derived beta-frequency oscillations (∼15 Hz). De France et al. 2003.. 1997. West & Grace. The signal-to-noise ratio hypothesis is a computational theory based on the idea that DA facilitates the selection of Nacc competing neuronal ensembles (Pennartz et al. .. 2005). DA transmission desynchronizes slow rhythms and induces fast-wave oscillations within the BG-thalamocortical circuits (Brown & Marsdan. 2000. 2003.. and promotes the emergence of high-frequency gamma oscillations (>60 Hz). local field potential studies support the hypothesis that DA promotes the emergence of characteristic rhythms and their diffusion in the brain: 1.. 2006). Dostrovski & Bergman. Sharot et al. Such network effects may offer the best overall explanation of DA induced psychobehavioral arousal (Steriade. 1998. DA modulation of global field dynamics It is remarkable that cognitive. 1994. 2000. 2002).. 1999.. 2002. Brown.. Collectively. 2001. enhances the signal-to-noise ratio in neural networks. 2003. In other words. 2004. 1999). Author manuscript. and (3) Concentration: evoked concentrations of DA in the range of 600 nanomolar (nM) elicit excitation (Gonon. The prevalence of beta rhythm in BG-thalamocortical circuits is associated with motor impairments characteristic of Parkinson disease (Deuschl et al. Magill et al. 2003.Lewis & O'Donnell. Brain Res Rev.Groenewegen et al. 2003. Gurney et al.. influencing long-term memory processes (Wise.Groenewegen et al. 2001.West et al.
2003).. We will next explore the possibility that gamma rhythms favor the release of specific neural activity patterns expressing intentional behavioral dispositions.Alcaro et al. It has also been suggested that gamma waves preside over the emergence of active intentional brain states (Freeman. 2000. Viewed as impulses to act. 1990. GABAergic neurons also preside over the release of repetitive sequential patterns (or neurodynamic sequences) (Laurent. DA increases the multisecond temporal oscillatory patterns (from ∼30 sec to ∼ 10 sec) of BG nuclei's spike trains. 1999. Since rhythmic bursts have been interpreted as the result of spreading of cortical activity into BG nuclei. Page 19 2. Murer et al.3. Gerfen. available in PMC 2008 December 1. the GABAergic basal forebrain neurodynamic sequences direct activity consistent with the sequence. 2002. Brain Res Rev. Lewis. and increases the spectral power of these oscillations (Ruskin et al. 2002. attentive functions (Brown. Gurney et al. As demonstrated for gamma rhythms (Brown. 2001). Author manuscript. and “binding of sensory object features into a coherent conscious percept” (Engel and Singer 2001). Sharot et al. The generation of gamma rhythms is essential for synaptic plasticity and memory processes (Paulsen and Sejnowski 2000. 1987) and in the promotion of high-frequency rhythmic oscillations in the gamma band (Llinas et al. 2006). but from instinctual behavioral and emotional drives originating in midbrain and hypothalamic areas and communicated through DA within BG-thalamocortical circuits. 1989. 4. 1990. 1997. DA suppresses slow firing oscillations and regular bursting of BG neurons (∼ 1 Hz) in anaesthesized and sleeping rats (Pan & Walters. these changes may reflect a barrier between cortex and BG. Sederberg et al. while their alteration has been observed in neuropsychiatric disorders (Herman & Demiralp. voluntary movement execution (Cassidy et al. 2005). 2005). Countermanche et al. 2005).. Steriade 2000). 2001. Albin et al. 2003). Capturing brain activity within dynamic attractors (Freeman 2000.. 2001). motivated behaviors do not arise from cognitive signals activating executive motor plans. 2004. it is reasonable that ML-DA favors the release of basal forebrain neurodynamic sequences reflected within fast-wave oscillatory gamma rhythms. Beggs & Plenz 2003.. MacLeod et al. they translate neural activity into the intentional code13 necessary for active movements. The intrinsic organization of these areas evolved to favor the emergence of sequential activity patterns that may be easily translated in movements because of their procedural shape... The DA capacity to promote gamma rhythms needs specific attention.. and constitute the intrinsic structure of intentional behaviors and cognitions. Gerfen et al... DA transmission relieves thalamic and brainstem 13We refer to intentional code as the dynamic structure of the neural activity produced in basal forebrain and basal ganglia areas. 2004. It is not known how GABAergic networks produce fast-wave rhythms and sequential neural activity patterns or the exact relationship between gamma rhythms and the release of neurodynamic sequences.. 2003. 2003). 2000. since these oscillatory waves are involved in diverse behavioral and psychological processes. Tseng et al.. 2006). Buzsáki and Draguhn 2004. 2001. optimal levels of DA are important also for the release of neurodynamic sequences14 (Stewart & Plenz. 1988... which underlie all of the above mentioned functions. Lagier et al. 2003. In sum. 2004). However. In classic theory of BG functions (Alexander et al. According to this view.. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 3. . In other words those areas have been predisposed to release coherent sequences of movements. DA effects on sequential neural activity patterns It has been shown that GABA neural networks are involved in the desynchronization of slowwave oscillations (Slovite.. 1986. 1991. 2003). Kuhn et al. the behavioral arousal function of ML-DA transmission may be explained on the basis of a DA-promoted emergence of high-frequency oscillations in BG-thalamocortical circuits.
4. Why not hypothesize then that the deep brain stimulation is effective because it restores basal ganglia characteristic oscillatory rhythms? 16But partially also by D1-type receptors belonging to hyperpolarized neurons of the direct pathway (Nicola et al.. phasic DA may increase their responsiveness to convergent descending excitatory influences (Gerfen. The SEEKING neurodynamic sequences presumably drive motor-action pattern generators via connections from ventral BG output to brainstem motor nuclei. 4B). However. p.. 17DA transmission tonically inhibits the entrance of glutamatergic descending input in BG areas either via D2-type receptors of striatal neurons belonging to the indirect pathway. They are the neural bases of instinctual internalized movements or action tendencies directed to actively investigate elements of the external and in humans perhaps the internal (mental) environment. 2003). glutamatergic input to basal forebrain and BG nuclei blocks neurodynamic sequences through the reciprocal GABAergic connections characteristic of basal forebrain ensembles. eye and head movements. 15The current interpretation of the therapeutic effects of deep brain stimulation is that such electric currents disorganize and blocks the activity of BG output nuclei. translating a general arousal state into active exploration. associated autonomic changes. Rather than conceiving DA behavioral effects as a consequence of BG output nuclei inhibition. They can not escape because when “one does manage to escape. when only a subset of basal forebrain neurons receives excitation (and this effect may be potentiated by DA transmission). West et al. it is interesting to note that the frequencies of such stimulations are around the gamma range (∼100Hz) (Garcia et al. Author manuscript. On the other hand. 2005). basal forebrain neurons are like the damned souls of envious kept in a cauldron. With a metaphor taken from Dante's Inferno.. SEEKING tendencies are comprised of specific types of locomotor activities. 2000. This may promote the release of neurodynamic sequences in accordance with specific information coming from corticolimbic structures (Fig.. as external stimuli continuously release new neurodynamic sequences. 2002. but not when normal BG oscillatory activity is restored through DA-facilitating medications or electrical stimulation15 (Garcia et al.138).Alcaro et al.. Brain Res Rev. In these cases. Page 20 nuclei from chronic inhibition by BG output nuclei. 2000. 2006). the others pull him/her back in! And so the cauldron closes itself” (Llinas 2002. leading neurodynamic sequences to be produced autonomously and without any input from the external environment. striatal neurons from the direct pathway (Nicola et al. while the activity of BG output nuclei is considered antikinetic. The overall DA inhibition of excitatory input. excesses of BG tonic DA transmissions may promote stereotypical behaviors and obsessive-compulsive disorders (Korff & Harvey... cortical. 2000). However.. we propose that DA transmission promotes highfrequency oscillatory patterns (Fig. BG output nuclei may rather exert an antikinetic effect primarily when they oscillate at low frequencies. via whole body exploratory sequences. Consistent with this view. mainly mediated by D2-type receptors of the indirect pathway of BG16 (Fig. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . Conversely. and other responses directed to attain perceptual information and to progressively orient the organism toward affectively enticing and eventually desired sources of stimulation (e. 1999). sensoryinformation sampling with continuous sniffing). allowing new information to enter basal forebrain/BG areas and new sequential activity patterns to be generated in BG-thalamocortical circuits. or via D1-type receptors of down-state. Nicola et al. DA arousal is supposed to emerge from a global increase in thalamocortical activity. 2004) and probably also Tourette's syndrome. ML-DA and the SEEKING neurodynamic sequences Limbic neurodynamics in the ventral BG serve as vectors for the expression of the SEEKING emotional disposition. 2005). 4B). and the release of BG neurodynamic sequences. Murer et al. available in PMC 2008 December 1. 2006). acting upon D1 receptors of depolarized striatal neurons belonging to the direct pathway.g. 4A). 2000). By integrating incoming 14Massive. This view may be contradicted by evidence where electrical stimulation of BG output nuclei relieves Parkinsonian symptoms (Hamani et al. an imbalance between phasic and tonic DA transmission may promote attention deficit hyperactivity disorders (Levy. BG-thalamocortical circuits of these subjects may be overcharged by switching signals. reduces the diffusion of cortical rhythms and promotes BG characteristic rhythms17.. Convergent glutamatergic input may thus form a switching signal (Redgrave et al.4. a behavioral coherent neurodynamic sequence is properly released. the abnormal presence of tonic DA may completely suppress the influence that cortical and limbic areas exert over subcortical nuclei.
2002. 2000. THE ML-DA SYSTEM IN DRUG ADDICTION 5. declines dramatically (White. it is also possible that SEEKING sequences actively contribute to the emergence ofpositive hedonic state – not sensory pleasure but euphoria. and empirical data. 1997). the neurodynamics of SEEKING sequences within BG-thalamocortical circuits should be viewed as essential neural integrative substrates for associative and operant learning processes. et al. Nestler. . Robinson & Kolb. From this perspective. 2005). The SEEKING neurodynamic sequences in the limbic BG-thalamocortical circuit interfaces continuously with other neural activities. Current theories Drug abuse has been defined as a chronically relapsing disorder. Indeed. 2002. the ventral pallidum. Going beyond formal models (Schultz & Dickinson. the rewarding value of external stimuli depends on the ability to activate such instinctual psychobehavioral sequences. By activating these sequences. Everitt & Wolf. However. Page 21 perceptual information into SEEKING action tendencies. Activity of the ML-DA 18SEEKING neurodynamic sequences may simply promote approach or operant behaviors via activation of motor routines. 2002. 2002). while the repertoire of behaviors not related to drug seeking. and the pFC. 2004. from molecular and cellular levels to neural circuits (Hyman & Malenka. 2001. As described in the next section. Author manuscript. White. The diffusion of SEEKING sequences in the BG-thalamocortical circuits brings about exploration and approach to the most prominent sources of positive affective stimulation. Brain Res Rev. where external environmental configurations gain the ability to activate SEEKING sequences.. pFC. hypothalamic and midbrain nuclei receive abundant direct and indirect connections from the NAc shell. Discrete operant behavior thereby becomes embedded progressively into ever narrowing SEEKING sequences. and perhaps largely affectively unconscious. and recovery. in which the addict experiences uncontrollable compulsion to take drugs. Instead of being processed in abstract algorithmic computations. 2004. Koob et al.. such a DA facilitated euphoria.. 2005). external stimuli may acquire an unconscious incentive value (Berridge 2004). acquiring incentive motivational value18 (via classical conditioning). the role of ML-DA transmission in learning emerges when such neurodynamics intermesh with other cognitive and perceptual representations (See Lewis (2006) for another elaboration of this type of view in emotion theory). emerge relatively directly from instinctual SEEKING dynamics (Panksepp. Niv et al.Alcaro et al. Raw emotional feeling may be highly linked to the neurodynamics that generate instinctual emotional behaviors. indicate that all these brain regions contribute to affective experiences (Panksepp. Dickinson & Balleine. In sum. 2005). considering the SEEKING disposition as the affective substrate for appetitive learning could have profound implications in understanding addictions. 2001. Therefore. we think that the SEEKING neurodynamic sequences are the procedural structures that concretely lead organisms to move across landscapes of perceptual configurations. Schultz.. available in PMC 2008 December 1. hippocampus. Chronic drug use causes permanent neural changes at many levels of analysis. it is likely that positive emotional affects. connecting the original configurations of stimuli to final reward configurations. 2004). taking. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 5. Waelti et al. the organism may coordinate its relationship with the environment in flexible ways. motor sequences that were stimulated by the presence of rewards and reward related stimuli become linked to the SEEKING sequences. When unexpected positive outcomes (sensory pleasures) emerge for a behavior in a novel environment. This forms a tight linkage between external stimulus configurations and the SEEKING urge. The development of addiction is attributed to the action of drugs in the brain (Leshner. amygdala. 2004. Perceptual information from both external and internal sources receive a preliminary evaluation of its survival value as it enters the NAc through limbic structure like olfactory bulb. 2005). Such behaviors eventually become habitual.1. when ML-DA arousal is no longer necessary to activate appetitite SEEKING urges (Choi. such as conditioned place preferences.
. drive mechanistically the behaviors of addicts without the involvement of any hedonic-homeostatic process (Shaham et al. 2003. 1996b. or compulsive drug seeking and taking despite adverse consequences” (Nestler. Hyman & Malenka. much of drug abuse may reflect self-medication to alleviate aversive feelings. Li et al. drugs gradually acquire a tremendous motivational power. p119). level. Brain Res Rev. as organisms become captivated by drug-related activities. Robinson & Kolb. and is defined “as a loss of control over drug use. Moreover. with commentaries). Thus. which is a powerful evolutionary force for creating social bonds. 2000. 1980) analysis. if not cognitive. As a “hedonic homeostatic dysregulation”. Koob & LeMoal. In fact. 2005). drug abuse has a cyclic and progressive nature and is characterized by a pathological alteration of the reward state. 2004. The emotional aspects of addiction are typically underemphasized. Author manuscript. Di Chiara 1998). The “opponent process theory. 2006). 2001). Relapse is then interpreted as the result of unconscious associative memories that.” Solomon (1977) proposed that drug abuse arises substantially from homeostatic imbalance caused by compensatory adaptations to chronic drug usage. 2002. the risk of relapse. and hence addictive tendencies. 2001. 2001a. Robbins & Everitt. arising from repetitive DA stimulation. 2001b. 2005 p1414). Initial studies of drug abuse in the 1960-1970s considered dependence as the cardinal feature of the disease. Koob. Nestler. most common drugs of abuse stimulate the release of DA. endogenous opioids mediate the rewards of social reunion. 2003. once activated.Alcaro et al. re-exposure to drugs or drug-related stimuli reinstates drug-seeking behaviors more strongly than withdrawal (Stewart & Wise. which modulates both their rewarding and the psychomotor arousal effects (Wise & Bozarth. 1987. Drug addiction is now diagnosed exclusively on the basis of observable “behavioral abnormalities”. Kalivas et al. partly engendered by drug withdrawal (see Khantzian. 2001. Dependence is the physiological state of organisms necessitating continuous drug intake to avoid withdrawal symptoms. . remains very high” (Hyman. Specifically. often precipitated by drug associated cues. 2002). where the neurological substrates of drug addiction are strongly linked to the natural social-emotional reward processes of animals that are always experienced at the affective. are involved in the development of compulsive drug-taking behaviors (Berke et al. 2005. Berke & Hyman. 2002. In the neurocognitive behavioristic perspective. 2003). available in PMC 2008 December 1. White. 1999. 1998.. Concurrently. Hyman et al. Panksepp and colleagues (1978. 1997. Di Chiara & Imperato. This perspective has also been adopted by Koob and his coworkers who have sought to identify the neurochemical processes directly involved in generating dependence (Koob & LeMoal. In other words. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 19The relevance given to associative learning overlaps the emphasis on overt behavioral expression as the only appropriate level of analysis. 2003). the affective-homeostatic perspective fails to explain why “after prolonged drugfree periods. Addiction is thus viewed as a “pathological usurpation of the mechanisms of reward-related learning” (Hyman. et al (1978.. well after the last withdrawal symptom has receded. 1992). in animal models. Such a conclusion is not probably from the Panksepp. 1980) envisioned that the natural negative emotional processes that sustain drug addictions is related psychologically to the separation-distress process that young animals exhibit when isolated from their caretakers. 2001. Criticism of the affective theory of drug abuse relates to the presence of relapse episodes. 1999. drugs act on the neurochemical processes involved in the formation of associative and procedural memories (Di Chiara. the deficit in reward functioning throws organisms into a “spiraling distress cycle” and drugs become necessary to restore the normal homeostatic state (Koob & LeMoal. Nestler. This interpretation has received support from work showing many common molecular pathways in addiction and memory processes19 (Nestler. 2003). 1988.. As a result of ML-DA hypofunctionality. Through the complex reorganization of brain circuits. Page 22 system represents a key aspect of the chain of events that leads from a molecular action of drugs to the establishment of compulsive habits. Permanent functional changes in the ML system and in BG-thalamocortcal circuits.
Koob. a study of sensitization should foster our understanding of why drugs and drug-related stimuli acquire an increasing motivational and incentive value (Robinson & Berridge. especially that of psychostimulants. “contextindependent sensitization” may reflect the increasing ability of drugs to activate the ML-DA system.. 2002). 1989. 2000. 2004). Ungless et al.. 5. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . also exists after repeated drug usage (White & Wang. Page 23 A widely heralded attempt to integrate this approach with a motivational perspective argues that repetitive drug usage causes a sensitization of the ML-DA system (see next paragraph). And this happens not just for drug rewards. Henry et al. 1999). 1993. which inhibit DA cell firing. 2004).. 2004. 2001. It has been shown that previous drug use. “Context-dependent sensitization” can thus be used to explore how drug-associated stimuli acquire their incentive value. they are getting more effect from a smaller amount of drug. In such cases. or the ML-DA response (“biochemical sensitization”) to a subsequent acute dose of the same drug (Vandeschuren & Kalivas. Author manuscript. It also provides an explanation for the phenomenon of relapse. increases locomotion. a pure incentive sensitization view might wrongly predict that addicts consume less drugs as their system gets sensitized to it. 1993. On the other hand. 1993. 2000. Since enhanced behavioral and ML-DA responses to drugs correspond to the enhancement of rewarding properties. 1969. 2000. Sax & Strakowsky. Vezina. Morgan & Roberts. Janowski et al. 1980). 2003). as predicted by the hedonic homeostatic dysregulation hypothesis (Koob & LeMoal. 2001. especially social ones (Nocjar & Panksepp. 2000. but a variety of natural rewards (Nocjar & Panksepp. Moreover. it is possible that the specific response to the pharmacological action of drugs is potentiated in some way or that the activity of the ML-DA system is globally increased after drug use. A subsensitivity of D2 autoreceptors. stereotypic responses (“behavioral sensitization”). The concept of sensitization was originally utilized to describe the fact that the application of electrical stimuli induces a “progressively excitable neuronal locus” showing an enhanced sensitivity to subsequent application of the original stimulus or associated cues (Goddard et al. 2001). 2000. Kalivas 1995).2. 2003. Wolf et al.. which is involved in mediating the incentive salience of external stimuli (Robinson & Berridge.. 1984. 2000.. 1989). Vezina et al. Weiss et al.. Furthermore. 2005. 2003). 1997. Kalivas et al. Volkow et al. available in PMC 2008 December 1. It has been shown that repetitive administration of psychostimulants causes an increased activity of midbrain DA neurons (White & Wang. Although a general enhancement of ML-DA functions after chronic drug treatment has been postulated (Robinson & Berridge. 2007). The addiction cycle One of the big problems in addiction studies concerns how compulsive habits get established from the occasional use of drugs.Alcaro et al. molecular and cellular adaptations responsible for a sensitized DA activity have been found in the VTA (Vanderschuren & Kalivas. 2002). The attractiveness of drugs and drug-associated cues depends on the capacity of those cues to activate a motivational appetite (“wanting”) through the stimulation of the ML-DA system. The process of sensitization is now considered a key step in the addiction development cycle where repetitive drug intake further enhances the desire to consume drug and further lead to uncontrollable urges. 2004) or along DA projections.... a deficiency in ML-DA transmission and consequent motivational changes have been observed Brain Res Rev. and has had little to say about the emotional characteristics of brain states. adequate evidence of enhanced ML-DA release under basal testing conditions in chronically drugged animals is missing. This theoretical perspective focuses on the influence of the sensory and perceptual processes that regulate the SEEKING urge. where drug-associated memories maintain the ability to activate the ML-DA system long after the withdrawal has subsided (Shaham et al. 2003). Namely. without contributions from external stimuli (Patridge & Schenk. On the contrary. 1984. Borgland et al. Sensitized responsiveness to drugs often depends on particular stimuli and environmental conditions previously associated with drug intake (Robinson & Berridge..
it is difficult for ML-DA sensitization theories to explain why the rewarding power of drugs is enhanced. drugs of abuse. the disposition to seek and explore. 2000). This process will cause repetitive and abnormal learning until the motivational and behavioral repertoire of organism becomes thoroughly captivated by drug-related activities.Badiani & Robinson. et al. 1997. a DA-induced activation of the SEEKING urge will help the animal to both achieve its goal and to learn from its current experiences. arise. such as the euphoria and exhileration of exploration and reward pursuit. this emotion is characterized by neural. The role of the SEEKING disposition in mediating drug-reward is indicated by the similarity between the unconditioned effects of drugs and those of novelty.3. 2004) may lead drug-related memories to acquire an increasing motivational value (Robinson & Berridge. 1998.. Novelty may be considered the unconditioned stimulus to which the SEEKING system is naturally predisposed to react (explaining why novelty promotes exploration). through which motivated behavior are normally expressed and certain positive affective feelings. 2004).. 1998. 1999. Weiss et al. As environments become increasingly familiar. Interestingly. already active in the presence of novelty. 2000). 2002. two different and opposite molecular pathways activated by drugs have been discovered (Nestler. changes responsible for a sensitized DA responsiveness to drug and drug-related stimuli (Vanderschuren & Kalivas. our view is centered on naturally occurring internal affective states. especially psychostimulants. bringing about the experience of novelty and of its associated euphoric effects. However. 2005. Moreover. our perspective attempts to specify that the appetitive motivational component stimulated by drugs is an ancestral emotional urge (the SEEKING disposition) regulated by DA transmission and characterized by specific neurodynamic patterns along ventral striatum and ventral BG-thalamocortical circuits. On the other hand. 1992. drugs of abuse will continue to activate the ML-DA system pharmacologically even in familiar situations. 5. is further activated by drugs. 1981b. which are being related to the experience-dependent motivational power of drugs. Koob & LeMoal. Strong associative memories between the SEEKING disposition and drug-related stimuli create the neural conditions for drugs to progressively increase their incentive value.. 1995. 2005). behavioral and affective components linked together in complex and synchronized ways. such as endogenous opioids. in this view. available in PMC 2008 December 1. 2002. compensatory adaptations responsible for a decreased ML-DA functioning induce motivational impairments and loss of interest in activities not associated with drug consumption (Koob & LeMoal. affectivity in our view is conceptualized not only as a result of homeostatic self-regulatory processes. 2002. Brain Res Rev. The affective neuroethological perspective of addiction Like the affective-homeostatic perspective of Koob and his coworkers. Nestler. 2004). while drugs activate the same system in a pharmacological way. Aston-Jones & Harris. Indeed. drug-related memories push organisms to consume drugs primarily by activating NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 20Commonalities between novelty and drug reward explain why addiction is so pervasive and difficult to stop. Nestler. Page 24 after repetitive drug use (Parsons et al.Alcaro et al. Volkow. 1987) and with the “incentive-sensitization theory” of addiction (Robinson & Berridge. Moreover. the SEEKING disposition is not activated as intensely. 2001. 2003. On one hand.. as already noted. but also of basic intention-in-action type emotional dispositions (Panksepp. Author manuscript. 2004). 1991. In sum. However. . 2001b. Compared with the “psychomotor stimulant theory” (Wise & Bozarth. while natural rewards are commonly ignored by human addicts. We have envisioned how natural “social reward” chemicals. Nestler. participate in addictive urges (Panksepp.. if natural rewards activate the ML-DA system in unpredictable and novel situations. novel environments enhance the rewarding and psychomotor activating properties of drugs. Panksepp. leading to environment specific sensitization (Badiani et al. 2004). According to this perspective. From our point of view. 1997. Indeed. 2004). Barrot et al. provide an artificial way to stimulate the emergence of the SEEKING disposition. creating an amplified effect20.
2004). It seems unlikely to us that molecular and cellular adaptations observed after drug use correspond to the storage of specific information into a linear input-to-output way of processing (Fig. 2002. non drug-related activities.. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev. To the contrary. drugs will acquire an enhanced euphoria-producing (rewarding) power since the hypofunctional DA system is characterized by a deficient development of self-inhibitory mechanisms that usually counteract the neurochemical effects of drugs. whereby drug-related memories and drug-seeking behaviors become linked together (Fig.. 2006. but also increase the vigor of normal motivational. such as a pursuit of sexual and food rewards in rats (Nocjar & Panksepp. 2004). 2007).. We envision the SEEKING neurodynamics being the affective-action centered functional structures. when behavioral routines to find and consume drugs become part of epigenetic changes in the SEEKING dispositions (Ikemoto & Panksepp. 1998).. Indeed. Panksepp et al. by promoting an enhanced ML-DA responsiveness to drugs. 5B). and the placement of amphetamine directly into the Nacc. et al. Author manuscript. 5A). we think that those brain changes more likely affect the way global reverberatory activity patterns within BGthalamocortical circuits are generated. especially negative ones such as social separation distress (Panksepp. and more 22kHz USVs when returned to environments in which they received aversive drugs (Burdorf et al. and how they are related to incoming activity elaborated through the rest of the brain. cellular and synaptic learning processes stimulated by drugs could be related to the emergence of the SEEKING disposition. is effectively promotes 50 kHz USVs (Burgdorf et al.. In other words. We can imagine that SEEKING neurodynamics activated in ventral BG by drug-associated memories are progressively transformed into behavioral sequences associated with compulsive habits and expressed habitually in dorsal BG circuitry. A novel feature of this model is that it offers some unique unconditional indicators of SEEKING urges for monitoring drug desire and craving independently of formal conditioning paradigms (Panksepp et al. 2006). In particular. Such affective vocalizations may be capable of being used to track fluctuating affective changes during various phases of the addiction cycle (Panksepp. rat vocalizations may serve as an instinctual “selfreport” of appetitive drug desire or aversion. The involvement of the SEEKING disposition in the first stages of addiction is consistent with evidence that sensitization arising from repeated drug injections not only promotes the establishment of drug-seeking behaviors. in the way we think this disposition is manifested at the whole brain/mind level (as neurodynamic patterns emerging into ventral BG and spreading into BG-thalamocortical circuits).. 2002. 2002. available in PMC 2008 December 1. the affective neuroethological perspective provides a new way of envisioning individual vulnerability to psychostimulant addictions and perhaps other drugs as well. Burgdorf. The abnormal and continuous activation of the SEEKING disposition by drugs is also responsible for the consolidation of compulsive habits.. As highlighted in the next paragraph. 2004). 2006. especially the shell region. Molecular. 1981) permits a conceptualization of addiction vulnerability as the consequence of the cascade of natural but specific emotionalaffective liabilities. a deficit in the ML-DA may lead individuals to become compulsive drug consumers. 2001b. 2001a). et al. since rats exhibit more 50kHz ultrasonic vocalizations (USVs) when returned to environments in which they received rewarding drugs. Thompson et al. the 50kHz USV system is intimately related to ascending brain DA networks (Burgdorf & Panksepp. how they are supported by ML-DA transmission. In such cases. 1999). Page 25 the SEEKING emotional disposition (at least at the first stages of the addiction process). together with the knowledge of the neural circuits involved in other emotions (Panksepp. addicts may no longer seek drugs just because of subjectively experienced elevated desire and euphoria but because of the power of automatically expressed habitual stereotypical compulsive behaviors (that are also well suited to effectively alleviate withdrawal distress). An ethological description of normal SEEKING behavior.Alcaro et al. For instance. .
Criticism against these theories of vulnerability came from studies showing that novelty. 1993. Nestler. Shimosato & Watanaba. Author manuscript.. Page 26 5. 1955). Individual vulnerability An important issue in drug abuse research concerns why some individuals develop vigorous compulsive drug use after modest consumption of drugs. 1997. 2000. and.. 2004. individual vulnerability to drug abuse in animal models depends on both genetic (Carney et al. Vanyukov & Tarter.. Khantzian. 1993. 2000. 2000) look at drug-taking behaviors as instruments of selfregulation and thereby emphasize the relevance of affective feelings as signals of addiction relevant internal states. Robinson & Berridge. Klebaur & Bardo. 1993b.. available in PMC 2008 December 1.. Indeed. drugs of abuse may constitute an excessive source of stimulation for individuals with higher basal levels of arousal. These findings have been considered strong evidence for an endogenous sensitization of the ML-DA system. 1989)... Zocchi et al. Rouge-Pont et al. Therefore. 1991.. 2000). 2004). 1989. Grimm and See.. 1995) and environmental risk factors for addiction (Bowling et al. Indeed. 1998. Bowling & Bardo. 2003) as well as the “reward deficiency hypothesis” (Commings & Blum. Belknap et al. 1995. namely individuals characterized by lower levels of internal arousal who are strongly attracted to intense sources of stimulation (Zuckerman. 1994. 2000. 2005). more specifically. George et al. Nader & Czoty.and history-induced vulnerabilities (Kellogg.. Human family studies demonstrate that addiction's vulnerability is influenced both by genes and environmental conditions (Uhl. Vezina. 1976. 2004). 1999. Kabbaj et al. de Jong & Kloet. 1976. A challenge to the endogenous sensitization hypothesis has emerged from experiments in which high responding rats have a slower rate of DA release and uptake in the Nacc compared Brain Res Rev. In accordance with such views. 1991. 1993. Piazza & LeMoal.. generating unpleasant states in them. they have been described as noveltyseekers (Bardo et al.Alcaro et al. 2002. Stansfield et al.. True et a. 2004). Gardner. Indeed.. individuals with a lower endogenous DA transmission may be preferentially attracted to the hedonic effects of drug-promoted arousal of the ML-DA system. vulnerability to addiction has been seen as the result of an endogenous deficiency in the reward state. either in individuals with genetic. HR) present an increased firing and bursting activity of ML-DA neurons in basal conditions (Marinelli & White. animals that are more vulnerable to developing drug self-administration show higher levels of behavioral activation after drug intake (Piazza et al. Orsini et al.. 2000.. Meliska et al. On the other hand. It has been demonstrated that vulnerable animals show higher locomotor and exploratory activity in novel environments (Piazza et al. the “self-medication hypothesis” (Markou et al.. Dellu et al. 2000). 1992b. This effect is explained by a greater drug response in the ML-DA system of these individuals (Bradberry et al.. Rouge-Pont et al. Pierre and Vezina. 1992). since drugs may constitute a way to compensate for endogenous arousal deficits and to pharmacologically increase internal levels of activation. rats selected for high responsiveness to novelty and psychostimulants (high responders. 1996).and drug-seeking rats are characterized by overactive ML-DA neurons (Marinelli & White. Marinelli & White.... 1996. Weiss et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . since positive affective states are influenced by arousal following an inverted-U shaped function. 1993. 1995. Because of their preference for novel environments (Dellu et al. 2003. 1993a. 2000). in laboratory animals. 1990. 1996.. Similarly. and has been suggested as the cause for increased activating and rewarding properties of novelty and drugs. Cabib et al. 1998.. Such endogenous sensitization has been attributed to a potentiation of synapses connecting glutamatergic excitatory projections and DA neurons in the VTA. 2003) or in acute withdrawal from drugs (Parsons et al. Misra & Pandey.. 1997. 1999.4. Kempf. 1999. low basal levels of ML-DA are related to drug-seeking behaviors. in the ML-DA functioning. Deroche et al. Hooks et al. 1996. 1991. 1999) and compared to human sensation-seekers. In an attempt to maintain “optimal levels of arousal” (Hebb..
2004. protecting them against the rewarding effects of cocaine (Morgan et al.Volkow et al. It is easy to speculate that it may have developmental origins... show fewer or less functional D2 autoreceptors (White & Wang. Harsing & Vizi. In sum. 1997. the lower expression or functionality of self-inhibitory processes in the ML system may compensate for the endogenous hypofunctionality of ML-DA transmission. 2002). 1987. In situations where unusual stimuli. 2000) may then be caused by a deficiency in DA transmission and may arise from the diffusion of cortical synchronized activity.. .Wilkinson. On the other hand. such as drugs of abuse or novel environments. induce a consistent release of DA into the Nacc and related basal forebrain regions. 2002. 2005). after drug experiences. exhibit lower levels of DAT in adulthood compared with controls with direct implications for greater responsiveness to drugs and stress (Meaney et al. 1988. it is not clear where this deficit arises. 1997). the deficiencies in the inhibitory mechanisms in the ML system will cause abnormally elevated DA responses. 1996.Nader & Czoty. 1982. 1997. Therefore. 1990. GABA projections into the VTA exert a general inhibition on DA cell firing (Hyland et al. DA usually reduces the amount of glutamate released or the intensity of glutamate-evoked cell firing (Siggins... 2004). it remains to be established why individuals with a blunted ML-DA transmission should present an enhanced ML-DA response to drugs and novelty.. O'Brien et al. the ML system may then be regulated by those neurodynamic patterns forming the procedural structure of intentional behaviors.. 2003). 2002).. 23Although the existence of an endogenous hypofunctionality of ML-DA transmission is considered the first link in the chain.. 1996... and prefrontal DA transmission exerts an inhibitory control over DA release in ventral striatal areas (Deutch et al. It has also been shown that the pFC DA response to amphetamine in the C57 “vulnerable” mice strain is considerably lower compared with that of the DBA addiction “resistant” mice strain (Ventura et al. 2001). 1981) and in BG output nuclei of Parkinsonian patients22 (Wichmann & De Long.. GABA inputs permit the progressive accumulation of DA molecules in the presynaptic vescicles and the increase of quanta of DA released per impulse. Keeping the DA neurons in a hyperpolarized state. The prevalence of glutamatergic transmission in the VTA and higher ML-related regions may also cause the spreading of slow-wave cortical rhythms into the midbrain and BG. 1984. Author manuscript. 2002). 2002).. Dray. 1980. The greater electrical activity of DA neurons (Marinelli & White. Yim & Mogenson. the ML-DA system will became less capable of self-regulating its own activity. An important consequence of endogenous DA hypofunctionality is the reduced expression of neuronal self-inhibitory mechanisms in the ML system. 2003). 1986. GABA transmission promotes the emergence and the diffusion of basal forebrain and BG oscillatory rhythms. as manifested in animals treated with chloral hydrate (Steinfels et al. which are more vulnerable to addiction. Maura et al. 1978.Karreman & Moghaddam. Although basal levels of DA are restored. Moreover.Uhl. If the ML-DA deficiency is one predisposing factors in addiction vulnerability23. Indeed. Under GABA control.Seale & Carney. Page 27 with low responders (Chefer et al.. based either upon genetic or environmental factors. 2002.King et al.. 1986.. 1991). low DA levels should be accompanied by a prevalence of glutamatergic transmission and a hyper-excitability of DA neurons to glutamate. Maternally separated rats. The increased bursting activity of DA neurons (Marinelli & White...Cabib et al. Mice of the C57 strain (the addiction vulnerable phenotype) not only show lower levels of D2-autoreceptors in the VTA (Puglisi-Allegra & Cabib. Ventura et al. Brunelle et al. it is also true that sensitivity to the rewarding effects of drugs forms a key component (de Wit et al. 2004). 2000) thus correlates with a less rapid DA transmission in projection areas21 (Chefer et al. Vulnerable individuals.Alcaro et al. 22On the other side. Brain Res Rev. vulnerable individuals may experience greater rewarding NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 21It is interesting to note that the same paradoxical correlation is present in animals chronically treated with drugs. Since DA influences the responsiveness of ML cells to external input. socially dominant monkeys present higher levels of D2 receptors. 2003). Jentsh et al. 1998. Bradley et al. 1991. but also a reduced concentration of DA transporter proteins (DAT) responsible for the re-uptake of extracellular DA in ventral striatal areas (Janowski et al. Therefore. available in PMC 2008 December 1.
Although we have not focused on this aspect of the ML-DA seeking urge. In its primal form the ML-DA-SEEKING system can generate a special kind of positive affect that is characterized by a euphoric engagement with the world. Author manuscript. from the excitement of anticipating monetary rewards (Breiter. leading to feelings such a cravings and excessive feelings of urgency. Page 28 effects of drugs. As this paper was completed. to the delights Brain Res Rev. we would propose. Knutson. such as “reward prediction error” which do not clearly envision or recognize the energetic psychobehavioural states this system mediates. and thereby establish realistic and adaptive expectations. a whole issue of the journal “Psychopharmacology” (2007. emotional network functions (Panksepp. Many theories of ML-DA still envision this system participating in goal-directed behaviours in relatively passive cognitive ways. might have difficulty generating comparably straightforward predictions. perhaps some subcomponents more than others. rather than what these systems are passing on in the global regulation of behavioural states (Panksepp. partly. and new findings and theoretical interpretations are emerging at a steady pace. Most eletrophysiological studies have been characterizing what DA neurons are listening to. In our affective neuroethological perspective. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript When the system “crashes” because effective reward-seeking is thwarted. 6. This system. Those alternative views remain encumbered by the failure to sift correlates from causes. especially the neurocognitive “teaching signal” views. which are mostly elaborations of previous positions. It can readily accommodate and be synergistic with many of the more specific views that exist in abundance in the literature. issue 3) appeared that was dedicated to the topic. 1981 to Panksepp & Moskal. 2001. energized by the ML-DA system energizes a coherent organismic response to the world ((Panksepp. even though it may not be able to completely counteract a negative affective state that has been concurrently aroused by various punishing events that require the seeking of safety. truly a wide array of information. CONCLUSION The analysis of ML-DA functions has become an enormous field of inquiry. which emerge from related. To the extent that we can define the normal range of arousal of this system. due to a higher activation of the SEEKING emotional disposition. vol.Alcaro et al. animals exhibit depressive responses partly because of the emerging dysphoria producing dominance of dynorphinergic tone over the whole ML-DA SEEKING apparatus (Nestler & Carlezon. 191. also participates in protecting animals against the vicissitudes of their world (punishing contingencies) by promoting the seeking of safety. Our view openly acknowledges affective psychological changes. but poorly understood. available in PMC 2008 December 1.. . There is no need to modify our position with respect to the cornucopia of these additional perspectives. 2001). 2006). We have hardly touched upon the human brain imaging data that is beginning to highlight how important this system is in all varieties of appetitive human motivation.. it would be predicted that kappa-receptor antagonists might not only be excellent antidepressants but they will tend to restore SEEKING urges in the behaviorally dysfunctional syndrome of clinical depression. et al. Most other theoretical perspectives of the ML-DA functions. It is also likely that excessive arousal of this system may be experienced as affectively extreme. we would suggest that it routinely tends to promote an affectively positive engagement with the world. 2005). et al. We would simply highlight that the view advanced here is one of the earliest and most holistic attempts to conceptualize how transhypothalamic reward circuitry. 2005). the ML DA is part of a general purpose appetitive foraging system (the SEEKING system) that allows animals to become acquainted with the diverse configurations and reward of their environments. 2007).
such views have difficulty specifing which kinds of actions are modulated by ML DA. Nicola. appetitive approach patterns. some of the new wave of “neuroeconomic” brain imaging goes back to animal work affirming the appetitive nature of some of the spontaneous signs of ML-DA arousal. 2007). since we considered the procedural routines represented in dorsal BG as learned subsequences of the SEEKING disposition that have become habitual NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev.. ii) 50 kHz FM USVs. Author manuscript. Several recent publications exhibit a growing interest in integrating dorsal BG DA and ventral BG DA behavioural functions (Robbins & Everitt. 2002). 2007). Nicola. Such unconditional indices. unconditioned) action tendencies.e. 2007). 2007). Such important questions recur in many of the most recent theoretical papers. 2005). et al.. available in PMC 2008 December 1.Alcaro et al. as an initial step. . above and beyond DA release. Thus. since there is no evidence that “stimulusevoked firing of DA neurons encodes specific movements” (Nicola. seeking and approaching movements when coupled with various external stimulus representations that have been experienced in the context of reward aquistions. 2007. psychobehaviorally represented in ventral BG-thalamocortical circuits. Our model integrates dorsal and ventral BG DA functions in a new way. especially the “frequency modulated” (FM) variety is strongly affetced by ML-DA dynamics (Burgdorf. 2006) and music (Blood & Zattore.. such a 50 kHz ultrasonic vocalizations (USVs) in rats (Knutson. should help us better characterize how the SEEKING disposition helps various behavior patterns become part of the learned repertoires of animals —both “realistic” and “delusional” --as the brains of organisms try to make causal sense of the correlated events to which they are exposed. Most of the work in the field is still motivated by computational views of ML-DA functions (see Phillips et al. Obviously. et al. 1998). putative direct index of the arousal of this SEEKING system in rats is the appetitive invigoration of sniffing (Clark & Trowill. Many modern theories of ML-DA function still reflect the old battles between behaviorists and ethologists (Burkhardt. we have at least three measures of spontaneous arousability of the SEEKING urge in rodents: i) sniffing. Thereby DA transmission rapidly becomes enmeshed in all varieties of object relations that allow animals to effectively pursue all exteroceptively detectable resources needed for survival. 2007. focusing largely “on a role of phasic dopamine in controlling the discrete selection between different actions” (Niv et al. the two views must work together. it needs to be reaffirmed that. and they need to be integrated into a seamless whole. These issues have been well reviewed elsewhere (Knutson & Wimmer. et al. the activating effects of DA is translated into instinctual (i. However. 2001. only single-neuron electrophysiological findings are presented as new empirical evidence without consideration of global-field dynamics studies that first revealed their usefulness in understanding Parkinson's disease. Page 29 of love (Fisher. Phillips et al.e. promoting the emergence of specific neurodynamic sequences first associated with instinctual exploratory and with learning. 2007). expectancy-type. 2007). operant responding) on fixed interval schedules of reinforcement (Panksepp. 1971). 2007. exhibit scalloped. 1971) and this measure exhibits spontaneous temporal conditioning that helps explain why animals behave the way they do (i. Such sequences lead to explicit orienting. 2001)... 1981. and generally support the long-standing thesis that has been updated and mechanistically developed here. In its primal form. since DA-promoted high-frequency rhythms facilitate the release of SEEKING neurodynamic sequences. Moreover. Another. Indeed.. the ML-DA energized brain SEEKING system provides a “goad without a goal” (Panksepp. organisms do have certain complex behavioural abilities before those abilities get re-structured and channelled by learning. and iii) general exploratory-foraging activities. How the behavioral activating effect of DA may be translated into specific motor patterns? Which kinds of actions are represented in the Nacc and other ventral BG areas? How are such actions adaptive in novel environments? In our affective neuroethological perspective. This vocal index of positive social engagement.. Unfortunately..
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. available in PMC 2008 December 1. Page 63 NS-DA system nigrostriatal dopamine system NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Nacc nucleus accumbens pFC Prefrontal Cortex TD Temporal Difference models VP ventral pallidum VTA Ventral Tegmental Area Brain Res Rev.Alcaro et al. Author manuscript.
ACC = anterior cingulated cortex. VP = ventral pallidum. MeA = medial nucleus of the amygdala. Haber & Fudge. HC = hippocampal complex. . BLA = basolateral amygdala. Author manuscript. Higher forebrain: pFC = prefrontal cortex. the structures innervated by ML-DA have been divided in dienchephalic. 1982. Brain Res Rev. 1993.Alcaro et al. CeA = central nucleus of amygdala. German & Manaye. LMB = lateral mammillary body Basal forebrain: Nacc = nucleus accumbens. Midbrain: VTA = ventral tegmental area Diencephalon: LH = lateral hypothalamus. LS = lateral septum. BNST = bed nucleus of stria terminalis. Page 64 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. According to anatomical and evolutionistic criteria (Swanson 2000). 1997). available in PMC 2008 December 1. OT = olfactory tubercle. basal forebrain. and higher forebrain areas. The ML-DA system The figure shows a schematic representation of the main forebrain areas reached by the mesolimbic DA system (Swanson.
The figure doesn't show the segregation of BG-thalamocortical circuits described by Alexander and coll. In such a way. available in PMC 2008 December 1. Figure 2.Alcaro et al. DA innervation of BG-thalamocortical circuits All ascending mesencephalic DA projections innervate the BG rather widely. our paper is mainly focused on the role of DA release in BG. while only the ML-DA system projects to the frontal cortex. but the schematic representation can be applied to limbic. (1986). DA transmission in ventral and dorsal striatal areas (the input areas of BG) modulates the communication between glutamatergic projections arriving from frontal cortex and GABAergic neurons located inside the striatum. Author manuscript. . associative or motor loops of those circuits. Although the DA transmission in frontal cortex has received an increasing interest. In particular. DA regulates the diffusion of neural activity patterns within basal ganglia-thalamocortical circuits. Page 65 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Brain Res Rev.
NIH-PA Author Manuscript Brain Res Rev. Without questioning the validity of the Grace theory. . The first one is well experimentally demonstrated. without strongly modifying the absolute phasic DA. 2000). a positive feedback loop has been hypothesized (but not demonstrated yet). whereas our model individuates the existence of a positive feedback loop. to distinguish it from the absolute phasic DA transmission. the Grace model emphasizes the existence of a negative interaction between tonic and phasic DA. The supposed positive feedback loop should act in longer time frames and consist in tonic DA increasing the amount (or quanta) of DA released per single burst. Page 66 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 3. it acts in short-time periods. our alternative model considers the existence of two different feedback loops between tonic and phasic DA transmission. in our alternative model. and inhibits the mean bursting activity of DA neurons. since its existence may help in explaining some important empirical evidence. We called this component the relative phasic DA transmission. However. In sum. since D2 autoreceptors activation decreases bursting (and firing) activity of DA neurons.Alcaro et al. Author manuscript. plus the mean bursting activity of DA neurons. and consists of the negative influences that tonic DA exerts over DA cell bursting (as in the Grace model). available in PMC 2008 December 1. tonic DA levels were indicated to inhibit phasic DA release. which is dependent upon the relative phasic DA. Functional feedbacks between tonic and phasic DA transmission In the Grace model (Grace 1991. In our model. tonic DA transmission increases the relative phasic DA (potentiating the efficiency of each burst).
DA inhibits cortically-derived beta oscillatory patterns and promotes the emergence of BG characteristic oscillatory patterns (in the gamma range) in BG-thalamocortical circuits (Brown & Mardsen. Brain Res Rev.. The consequent emergence of gamma and other BG rhythms may favors the release of neurodynamic sequences and their diffusion in BG-thalamocortical circuits. 2003. O'Donnell. 2003) (B). Brown.Alcaro et al. 2003) (B).. Those signals may control the release of neurodynamic sequences in accordance with the representation of the organismenvironment relationship... Author manuscript. 2004. since they have an inhibitory role over descending glutamatergic transmission into BG areas (Nicola et al. 2005). . DA-promoted BG activity patterns Much evidence has shown that the release of DA into BG blocks the spreading of cortical rhythms in BG structures (A). 2000. available in PMC 2008 December 1.. Countermanche et al. West et al.. On the other hand. 2003. For example. 2003. 2003. Sharrot et al. Lee et al. 2004. 1998. Magill et al. The inhibitory function of DA transmission on the spreading of cortical rhythms is mainly mediated by the activation of D2-type receptors (D2). The global function of DA may then be conceptualized as a widespread modulation favoring the elaboration of relevant corticolimbic information into a BG intentional code. transient activation of D1-type receptors (D1) may have an excitatory function and seems to favor the entrance of specific and highly convergent cortical and limbic information into BG (West et al. O'Donnell.. Page 67 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 4.
Once generated. Author manuscript. Therefore. Brain Res Rev. these sequences match the representations of specific information about the environment (which are elaborated in BG-thalamocortical circuits and related structures). while the ML-DA transmission (especially into the Nacc) is supposed to be particularly important in the drug-induced reinforcement process. we think that the match between SEEKING sequences and drug-related memories permanently modify the functional organization of the brain (from the molecular to the systemic level). we think that ML-DA release after drug intake facilitates the emergence of specific neurodynamic sequences along the BG-thalamocortical circuits. Page 68 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 5. . In particular. The affective neuroethological perspective advanced here diverges from the previous one in considering the drug-induced activation of the SEEKING emotional disposition as the cardinal element in the formation of those memories that make drugs and drug-related stimuli always more attractive (B).Alcaro et al. In line with the “Hebbian” dynamic conception of synaptic plasticity. which constitute the patterns through which the SEEKING disposition is expressed at the neural level. available in PMC 2008 December 1. the cascade of neuroadaptations observed after drug use (from molecular to cellular level) represents the tendency of the SEEKING disposition to be activated by drug-related memories and expressed through drug-seeking behaviors. The over-representation of drug-related memories should be caused by synaptic modifications connecting cortico-limbic areas (involved in the representation of motivationally relevant stimuli) to BG areas (involved in the expression of motivated and intentional behaviors). addiction has been explained as the consequence of drug-induced brain adaptations “stamping” specific associative memories in neural circuits (A). The flow of activity through which compulsive memories are expressed is a linear input-output way of processing. The process of drugs addiction development In the neurocognitive behavioristic perspective.
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