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Molecular Psychiatry (2000) 5, 467–475 © 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.



Is there an evolutionary mismatch between the normal physiology of the human dopaminergic system and current environmental conditions in industrialized countries?
L Pani
CNR Center for Neuropharmacology, ‘BB Brodie’ Department of Neuroscience, University of Cagliari and Neuroscienze Scarl, Cagliari, Italy
A large body of evidence has recently defined a field theory known as ‘evolutionary mismatch’, which derives its attributes largely from the fact that current environmental conditions are completely different from those in which the human central nervous system evolved. Current views on the evolutionary mismatch theory lack, however, any attempts to define which brain areas or neuronal circuits should be mostly involved in coding such misevolved traits and to what extent our neurobiological knowledge can be applied to the topographical localization of a specific psychopathology. In this respect the mesocorticolimbic dopaminergic circuits have long been misconceptualized as simple reward or reinforcement systems. Instead, they motivate and coordinate the functions of the higher brain areas that mediate planning and foresight and direct finalized movement in both animals and humans. These systems make animals intensely interested in exploring the world around them, but by the same means they also make them susceptible to the environmental stimuli that have been sought and consumed. It is has been speculated that the cortical dopamine targets that developed most recently in phylogeny are of particular functional value, and that the mesocorticolimbic dopaminergic system is involved in more complex integrative functions than previously assumed. In the present paper I will argue that some mental disorders may have their deep roots in the evolutionary mismatch between the normal physiology of the mesocorticolimbic dopaminergic system and the current environmental conditions in affluent societies. Molecular Psychiatry (2000) 5, 467–475. Keywords: evolution; limbic system; dopamine; stress; depression; emotions; Darwinian medicine

Introduction The essential steps in the evolution of the brain from early mammals1 to humans2 show an increasing motor3 and cognitive-emotional interaction4 with the external world (Table 1). This ‘environmental pressure’ required the development of a neuronal system which was able to decipher and cope with the signals and stimuli coming from the brain’s surroundings. In this sense, the utilization of ‘the principle of reward’5 by linking outcomes of behaviors to either reinforcing or aversing sensations (and memorizing them), which is part of the normal physiology of the dopaminergic system, was absolutely instrumental in the course of evolution. Several authors, however, consider such a view an over-simplification of the role of the mesolimbic and mesocortical dopamine circuits, which not only direct finalized movement in both animals and humans, but
Correspondence: Dr L Pani, CNR Center for Neuropharmacology, Via Porcell, 4, 09124-I, Cagliari, Italy. E-mail: panilȰ Received 3 January 2000; revised and accepted 10 April 2000

Table 1 Steps in brain evolution with increasing environmental interaction 1. 2. 3. 4. 5. 6 7. 8. 9. 10. Bipedalism Development of a cooling system Trichromatic vision Hemispheric dominance/use of tools Nursing and maternal care Voluntary control of speech Separation call Self/other feelings awareness Development of synthatic ability Pressure to speak

also motivate and coordinate the functions of higher brain areas that mediate planning, foresight and promote states of eagerness.6,7 By these functions animals become intensely interested in exploring the world around them, but by the same means they are exposed and susceptible to the environmental stimuli that have been sought and consumed. In mammals, and especially in primates, the mesocortical dopaminergic

18 These data suggest that a dopamine D1/beta receptor gene duplication was required for the elaboration of novel catecholamine psychomotor adaptive responses.11 It has been speculated that the cortical dopamine targets that developed most recently in phylogeny are to be considered of particular functional value. all the classical transmitter ligand molecules evolved the ability to activate a wide range of ion channels. but before the divergence of the avian and mammalian lineages. In the present paper I will argue that the evolved physiology of the mesocorticolimbic dopaminergic system may be mismatched with respect to current environmental conditions and may contribute to the precipitation of human psychiatric disorders. lamprey and hagfish. indicating that many of the basic receptor subtypes evolved at an early period. a moderate and reasonably steady rate of sequence change. In this respect. pharmacological. such synthesis is inhibited by alpha-methyl-p-tyrosine. One of the most rudimentary nervous systems. resulting in excitation. a drug of abuse that increases dopaminergic transmission. insufficient to result in such superior animal characteristics as the ability to feel pleasure and pain. forms a monophyletic group with both vertebrate dopamine D1 and beta adrenergic receptor classes. and that the mesocorticolimbic dopaminergic system is involved in more complex integrative functions than previously assumed. such as selective attention/predictive reward and emotional drive. a single catecholamine receptor gene was found which. that of the sea pansy Renilla koellikeri (Cnidaria). Recent investigations have confirmed that the dopamine D1A. warmth and sex.Evolutionary mismatch of the dopaminergic system L Pani 468 system generates and sustains curiosity. the ability of the catecholamine Evolution of the dopaminergic system Enzymes The acquisition of the behaviors modulated by dopaminergic innervation has been so indispensable in survival that the enzymatic machinery needed to synthesize dopamine appeared very early in phylogenesis. in the vertebrate phylum. water. the invertebrate receptors which have so far been cloned show striking homologies with mammalian receptors. have been conserved in their gross and microscopic structure throughout evolution from rodents9 to humans. most strictly involved in human pathologies such as depression and psychosis. Several results indicate that the first event to occur within this gene family was the divergence of the catecholamine receptors from the muscarinic acetylcholine receptors. at the cephalochordate/vertebrate transition.10 the structural organization of the cortical dopaminergic circuits. a sister group to vertebrates. D1B. shows significant differences between rodents and primates. Vertebrate neural pathways synthesizing monoamine neurotransmitters (mostly dopamine and noradrenaline) were subsequently recruited in order to process increased information demands by mediating psychomotor functions. In contrast. such as the nucleus accumbens and the caudate-putamen. In amphioxus. is able to synthesize dopamine. Rather. However.18 All these receptors conserve a fairly stable secondary structure. and D1C receptors share molecular. via the activation of multiple G-protein linked catecholamine receptor subtypes. the presence of dopamine (but not of noradrenaline) has been assayed. but the hyperkinesia induced by cocaine. which occurred prior to the divergence of the arthropod and vertebrate lineages. This appears to have occurred after the divergence of the arthropod and vertebrate lineages. and usually lack introns within their coding sequence. which are most likely to be used to capture food or avoid danger. and functional attributes that unambiguously allow for their evolutionary classification as distinct D1 receptor subtypes of the G-protein linked super-family. Subsequently.14 Goldfish show place preference for the water bowls where they have received amphetamine. a drug which blocks the dopamine transporter. At least 1000 million years ago (MYA).12 Recent data show that the major development of the cerebral cortex in primates was accompanied (or produced?) by a similar expansion of the dopaminergic input to all cortical layers. the second-messenger pathways activated by adrenergic and dopamine receptors did not diverge independently.13 In this invertebrate.11. including food. inhibition and biphasic or multiphasic responses. with a specific and laminar redistribution of the dopaminergic terminals. paralleling a high dopamine and noradrenaline content throughout their brain. probably around 800 MYA. two distinct genes homologous to the jawed vertebrate dopamine D1 and beta adrenergic receptor genes were shown to be extant in Molecular Psychiatry .17 The evolution of these receptor-mediated events was similarly driven by forces of gene duplication.16 Receptor family The evolving vertebrate nervous system was always accompanied by major gene duplication events which generated novel organs along with a definite sympathetic system which was needed to monitor and control them. It is particularly effective in memorizing information about where material resources are located and the best way to obtain the things needed for survival.8 While telencephalic dopaminergic nuclei.15 In the cephalochordate amphioxus. representatives of the earliest craniates. in Planaria specimens suggests that the selective site for pre-synaptic dopamine re-uptake is already present in this flatworm. based on molecular phylogeny and functional analysis. and it is quite efficient at facilitating learning. The neurochemical basis of the effects of dopamino-mimetic drugs in other distant organisms has not been fully elucidated. the ability to activate specific second-messenger pathways diverged independently in both the muscarinic and the catecholamine receptors. and that a noradrenergic system specifically emerged at the origin of vertebrate evolution. the role of dopamine is that of giving bioluminescence and producing muscular contractions.

by means of both incentive-salience and associative-learning. To explain the somatic correlates of such an evolutionary view of diseases. suggesting that the transcriptional control of the gene encoding for the dopaminergic receptors has also undergone profound changes throughout evolution. These dopaminergic systems are involved in those mechanisms which determine satiety to food.20 Table 2 Years of significant inventions and technological advancement 1550 1690 1770 1853 1876 1885 1886 1903 1920 1926 1948 1962 1969 1972 1978 1988 1992 2000 Screwdriver Steam engine Electrical battery Hypodermic needle Telephone Gas-engine auto Coca-Cola Airplane Radio broadcast Television Transistors Minicomputer Moon landing Videogames Test tube baby Patented animal life Global internet Human genome sequenced 469 The dopaminergic system and the mismatch theory Large sets of data (for a review see Nesse and Williams)21 have recently allowed the definition of a field theory called ‘evolutionary mismatch’. as well as a particular susceptibility to mental disorders. which derives its attributes largely from the fact that current environmental conditions in industrialized countries are completely different from those in which the human central nervous system evolved. dopamine neurons define the substrate for precise associative learning abilities. The mismatch between evolved traits and contemporary lifestyle. others have argued that mesolimbic dopaminergic pathways do not code for such an ability. a poor fit between strongly evolved traits (eg dependency) and the current urban social environment may account for the increase in frequency of anxiety and depressive disorders in modern societies. however. in the olfactory tubercle. and historical constraints (eg how a trait has evolved).23 sex. but serve only to respond to specific stimuli which possess high motivational impact. where change is mostly due to fast technological advancement (Table 2). and particularly in more recent structures such as the cerebellum and the frontal cortex. the most important dopamine systems involved are that of the terminal fields of the prefrontal cortex. According to the first hypothesis. is still a matter of intense debate. a definition of which brain areas or neuronal circuits should be involved in coding such misevolved traits.24 and drugs of abuse. rewarding (and thus also averse) stimuli that have acquired motivational significance (salience) are part of a phenomenon which is neither unitary nor subjective. In contrast. unpredictability. process. If the ever-mutating environmental conditions. Apart from these nuclei. and must facilitate. rat. dopamine. ie the attribution of incentive salience to an otherwise neutral event. The appetitive and consummatory phases of behaviors triggered by environmental cues which are associated with survival properties (whether rewarding or aversive for the individual) are known to be mediated by sensory-specific dopaminergic neuronal circuits. or cat is compared with that of a monkey. has resulted in the poor specialization of selected traits. or occurrence under a deprivation state. as a result of their novelty. the absolute and relative values of the dopamine receptor subtypes is completely different in primates. their rapid rate of evolution and change would impose a pressure that is not paralleled by an evolution of the brain structures which are able to analyze. the highest density being present in the caudate-putamen. and elaborate on such rapid variations.28 or the associative learning29 capacities of an event. and in the substantia nigra. dopamine-related neural circuits mediating only a specific component of reward.19 When the distribution of the dopamine D1 and D2 receptors in the brain of a mouse. This confirms that dopamine is an Molecular Psychiatry . norepinephrine. or octopamine.22 Current views on the evolutionary mismatch theory lack. it is assumed that pathogens that attack humans evolve faster than we do.25 In all these conditions. in the nucleus accumbens. specific sensory modalities.Evolutionary mismatch of the dopaminergic system L Pani receptors to bind to specific ligands. For example. Stimulation of the dopaminergic transmission will increase these behaviors. such as epinephrine. was repeatedly modified in evolutionary history. Whether the stimulation of these neurons mediates the incentive salience (reviewed in Berridge and Robinson). similarities are found only in the basal ganglia. the two mechanisms must play an equally important role in the attribution of an incentive value to ethologically relevant stimuli. and to what extent our neurobiological knowledge can be applied to the topographical localization of a specific psychopathology. and in some cases was modified after the divergence of the second-messenger pathways.29 in these conditions. From an evolutionary perspective. could now be assimilated to organic pathogens. The conservation of such principles throughout evolution explains why pharmacological manipulations of the dopaminergic transmission are similarly able to modify basic behaviors in distant species such as lizards and rats (Table 3). while the blocking of dopaminergic receptors or lesions of the dopaminergic pathways will decrease them.27 both originating from neurons located in the ventral tegmental area of the midbrain. the presence of evolutionary trade-offs (eg selection of some traits over others).26 and that of the nucleus accumbens. the selection and the memory of appropriate behavioral responses.

either with an increase in exploration (by means of curiosity and reward) or a decrease (through fear and aversion).32 This ability to see in color was instrumental in detecting ripe fruit. especially in industrialized countries. and gave an immediate evolutionary advantage over green-leaf eaters. the two most expanded structures in all species are. the system for emotional communication via facial expression expanded and the olfactory bulb completed its regression in primates.31 which I will consider as primary sites for the evolutionary mismatch between the dopaminergic system and the ability to process significant environmental-driven change-related information that guides coherent behavioral responses. In addition. 12. 11. and unipolar disorders were higher in the cohorts born after 1940 than in the cohorts born earlier. the number of visits during which a psychotropic medication was prescribed increased from 32. which doubled from 10 to 20 million in the last 5 years period. olfactory.Evolutionary mismatch of the dopaminergic system L Pani 470 Table 3 1. which has an important integrative function. nucleus accumbens and internal capsule). Electrophysiological recordings have indicated that key cortical and subcortical dopaminergic regions are involved in these motivated behaviors. At about the same time.33 When the sizes of 10 measured brain divisions from 131 species are plotted as a function of total brain size. 2.37 In the 9 years period between 1985 and 1994. Since these multimodal neurons were found in very close proximity to unimodal neurons. leading to an increase in prevalence of a broad spectrum of familial affective disorders in the coming decades. Recently. some neurons were found to possess a bimodal response.36 It was suggested that an ominous trend could be present. 9. Thus. previously the largest category. to both taste and olfactory. Antianxiety or hypnotic drug visits. for example. it appears that in current affluent societies the Expansion and regression of dopaminergic innervation Animals with big brains are scarce. development time. showing that a highly predictable relationship exists between the relative size of the neocortex and that of the total brain.35 Conditions that have changed through evolution and which interfere with the function of the dopaminergic system Empirical data suggest a causal relationship between evolutionary-new environmental factors. or visual systems. Neurons in this region of the cortex were indeed found to respond to stimulation of the taste. a particular role in primates is given to the connections between the nucleus accumbens and the frontal cortex. it is possible that the orbitofrontal cortex represents the first cortical area of convergence for these three modalities in primates. Among these. a Special forms of basic behaviorsa Establishing a ‘territory’ Showing place preference Hunting Greeting Social grouping Feeding and drinking Grooming Courtship Mating Breeding Maternal behavior Play (mammals only) Adapted from Reference 6. 8. These dramatic trends are in agreement with our findings (Table 4). where we consider the Italian sales of psychotropic medications classified into three major categories: anxiolytics. at variance with that of the olfactory bulb. 4. important neurotransmitter coding for sensory-specific responses. 5. in fact. and antipsychotics and confirmed a significant tendency toward increase for antidepressants (+34%) and antipsychotics (+15%) but not for anxiolytics (+4%) in the last 5 years. 7. the use of psychotropic medication in outpatient medical practice rose dramatically during the last 10 years.64 million. This prediction proved to be correct and confirmed by more recent reports where changes in the prescribing patterns of psychotropic medications by office-based United-States physicians were examined. in the sense that a perceived environmental clue is acted on cognitively. two heavily innervated dopaminergic structures—one coupled to taste related reward and satiety. schizoaffective. the neocortex and the striatum (caudateMolecular Psychiatry . a duplication of the gene coding for a retinal cone pigment in an ancestor of prosimians resulted in the development of trichromatic vision.73 million to 45. These complementary characteristics have been conserved in modern humans. Thus. putamen. and anatomical complexity. It was always supposed that a much better diet (in terms of caloric value) must have been the starting point for the development of a much larger cerebral mass. Accordingly. and the other to olfactory satiety—seemed to be mutually exclusive in their development. this hypothesis was confirmed. specific dysregulation of the physiological ability of the dopaminergic system to process environmental stimuli and specific psychiatric disorders. and since the unimodal sensory neurons were intermingled.30 but also show that the physiological responses of the dopaminergic system are strictly ‘environment sensitive’. 6. about 40 MYA. Recently it was described how. decreased and were surpassed by antidepressant visits. and stimulant drug visits increased more than fivefold in the same period. 10. Gershon et al showed that the rates of bipolar. 3. antidepressants. because bigger neuronal structures are more costly in terms of energy expenditure. Around 10 years ago. responding.34 The neural mechanisms of sensory-specific satiety in primates are implemented in the orbitofrontal cortex. or taste and visual stimuli.

51 and the failure of this coping mechanism may well contribute to the vulnerability of the medial prefrontal cortex in many neuropsychiatric disorders related to the stress response.40 to ‘both a survival mechanism and an indicator of internal and external cues’. purify and lately synthesize psychoactive compounds has increased their availability to the general population in quantities and qualities never experienced before in the history of mankind. and help to clarify its role in the general physiology of the central nervous system. playfulness. displacing all the other adaptive traits. The limbic portion of the dopaminergic system is essential for the generation of the basic emotions that mediate various pro-social behaviors.Evolutionary mismatch of the dopaminergic system L Pani Table 4 The Italian market for psychotropic compounds Millions of prescriptions per year 1995 1996 1997 1998 1999 Antipsychotics Antidepressants Anxiolytics 11 675 12 432 12468 12 940 13 428 16 750 18 275 19413 20 524 22 493 33 143 34 589 34093 34 917 34 487 psychological). the development of new routes of administration (eg hypodermic needles. Instead. If drugs of abuse that act on the dopaminergic system (that is all of them.46 and a loss of inhibitory tone on ventral tegmental area dopamine cells47 and lateral-basolateral amygdala (see below) as important regulatory sites for maintaining superior cognitive functions.52 Chronic emotional reactions Emotional responses can be difficult to differentiate from generic reactions to stress. water. Several data point to ventral tegmental area projections. in laboratory animals as well as in humans.43 The fine tuning of dopamine extracellular concentration in the medial prefrontal cortex seems to be essential for the decision-taking protocols of the medial prefrontal cortex in the rat and the monkey. the balance between cortical and subcortical dopaminergic activity may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult. actively change behavioral hierarchies. ie the pure ability to experience pleasure. would be the only one to be mainly affected by their chronic use. are profoundly altered in a drug addict. Drugs of abuse that convey a signal that falsely indicates the arrival of a huge fitness benefit (much higher than food. In addition. along with the emotions which are related to them and their cognitive implications. and numerous results suggest that mesoprefrontal cortex dopaminergic projections are selectively activated by sudden changes in environmental conditions. much more than just the capacity to experience pleasure or avoid pain (whether physical or Molecular Psychiatry . and has contributed to a change in the traditional relationship between the use of the natural source of the drug (eg the chewing of cocaleaves) to that of its active component (eg the endovenous injection of cocaine hydrochloride).44 This supports the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning. All these behaviors. after a variable period of use. The increased ability to remove dopamine in chronically stressed animals has also indicated that altered dopamine clearance may serve as an adaptive mechanism in the medial prefrontal cortex. ultimately.41 Both acute and chronic stress have a detrimental impact on the normal function of the dopaminergic system (for a recent review see Pani et al).45 dopamine receptors. organic solvents) has increased the penetration of drugs of abuse into the brain. producing not only an impairment of his/her hedonic capacities. Drugs of abuse offer a remarkable example of evolutionary mismatch at the level of the dopaminergic system. but also a more disruptive effect on the cognitive and emotional abilities that are necessary for an effective interaction with the external world (maladaptation).42 The response of the dopaminergic system to stress is neither homogenous nor generalized. disruption of the medial prefrontal cortex dopamine fibers may result in the altered biochemical responsiveness of the dopamine subcortical innervations. all drugs which determine a state of dependence interfere with the global adaptation of an individual to its environment. In addition. drugseeking increases in frequency to the point where it becomes the only dominant behavior. etc).48 It has been further suggested that increased dopamine D1 receptor stimulation during stress may serve to take the medial prefrontal cortex ‘off-line’. in order to allow posterior cortical and subcortical structures to regulate more ‘primitive’ forms of behavior. emotions such as 471 frequency of psychiatric disorders requiring medications which modulate the function of (and not only of) the dopaminergic system is increasing. the outcomes of acute affective disorders are considerably more favorable in developing countries than in comparable studies in developed settings38 where at least four areas of evolutionary novelty can contribute and will be briefly discussed below.50 In humans. In addition. Drugs of abuse The ability to extract. As a consequence. directly or indirectly) were used solely for their hedonic and ‘reward producing’ potential. to increase fitness.49 Since dopaminergic innervation of the medial prefrontal cortex is able to regulate the activity of subcortical dopamine innervations. sex. crack smoking. then this capacity. and friendship. and which have been learned and have evolved to influence motivational states and. with reduced or excessive dopamine turnover leading to cognitive impairment.39 Stress The definition of the term stress has gone from ‘a nonspecific response of the body to any demands made upon it’. such as maternal care. whether expected or not.

A dorsal tier of dopamine neurons receives input from the nucleus accumbens and from the amygdala. during which the animal presents a cohort of symptoms that appear to mimic those present in idiopathic mania. midbrain and hindbrain areas.67 These findings are indirectly confirmed by the increased use of neuroleptics (Table 4) which. poor physical activity. and projects widely throughout the cortex. Sleep deprivation in rats has been extensively studied as a possible animal model of mania. along with the central amygdala. and therefore impossible to mimic in animal models. the dopaminergic limbic system has an enormous influence on cortical output and can therefore affect the emotional and motivational ‘coloring’ of a wide range of behaviors. during this period the animal displays a high degree of hyperactivity. the application of a highintensity loud noise. into an unfamiliar environment.59 others demonstrate that longterm administration of low. today there are six billion of us worldwide.65 Accordingly. increased physical constraints. and to have a coordinated role in regulating the information flow between cortical structures. two selectively bred lines that differ in their level of emotionality. mediates conditional fear. Through its projections to forebrain.53 In this respect. are all associated with an increase in extracellular cortical dopamine metabolite levels in the RHA but not in the RLA line. In modern times this can be obtained by generic stress due to sleep disruption. albeit again strain-dependent. exploration and defecation have been considered as valid somatic correlates to human emotional responses in which the dopaminergic system is involved. is an essential function of the mesencephalic dopaminergic neurons.66 and that recurrent brief hypomania which lasts 1–3 days and belongs to the bipolar spectrum. overall. the central amygdala governs the behavioral. time shifts.68 Conclusions The brain of Homo sapiens sapiens developed on the African plains. the rat does not fall asleep as soon as it is returned to its home cage. produced inconsistent data. selfgrooming. direct evidence demonstrates that acute and chronic sleep deprivation may trigger a manic episode in otherwise healthy individuals.61 Chronic sleep deprivation Humans have conserved mechanisms. and unnatural social rules. and of their role in the organization of behavioral responses which are the reflection of a heightened attention of the animal attempting to cope with the stressor. Several studies from Wehr and collaborators62 have suggested that modern men’s use of artificial light after dark and artificial darkness during the daytime suppresses responses63 to seasonal changes in the duration of the natural scoto. In all the models. and endocrine responses that characterize a central fear state.60 In contrast. the chronic nature of the stimulus is essential to produce a stable change in the normal physiology of the dopaminergic system. the total amount of sleep. suggesting that the differently evoked emotional reactions may produce a common activation of cognitive processes. like those that exist in other animals. pre-synaptic doses of the dopamine D2 antagonist l-sulpiride is highly effective in an animal model of anticipatory anxiety/panic behavior. role for dopamine D1 receptors in mediating specific emotional behaviors. in populations of a few hundred thousand individuals. While some results suggest an important relationship between social and motor reactivity.64 Interestingly. at the end of the period of sleep deprivation (approximately 72 h).58 The study of fear and the role of the dopaminergic system in rodents have. are still the standard treatment for acute bipolar mania. according to the genetic makeup of an individual. is increasing in young adults.Evolutionary mismatch of the dopaminergic system L Pani 472 empathy seem to be uniquely human. several animal behaviors such as freezing. high-frequency electrical stimulation of dopaminergic nuclei of the ventral tegmental area. or immobilization. and stereotypy. producing a chronic disturbance in the sleep pattern and decreasing.and photoperiod that might otherwise occur at a given latitude. hyper-sexuality. Through these projections. In particular. recent findings suggest that quinpirole (a dopamine D2 agonist) decreases fear by blocking the retrieval of a learned association between a conditioned and an unconditioned stimulus. however. which detect changes in day length and make corresponding adjustments in the duration of nocturnal periods. although their use has been widely discouraged for mood disorders. the lateral-basolateral amygdala receives sensory input from environmental stimuli and. but shows a period of wakefulness of about 30 min. humans exhibit a constellation of emotional symptoms. It is time to ask ourselves whether the structural organization and the neuronal plasticity of the human Molecular Psychiatry . irritability. aggressiveness.55 The introduction of Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats.54 Accumulating revelations about the amygdala-based fear system has led to considerable progress in delineating the neural connections and cellular mechanisms that underlie aversive emotionality. In diseases in which dopamine function is compromised. autonomic. suggesting that the dopamine system plays an important role in the integration of superior cortical functions. as well as an important.57 The mesocortical dopaminergic innervations seem to facilitate the functions of integrative structures. In spite of this.56 This difference in reaction to a stressful stimulus. The model allowed the discovery of an active role of limbic dopamine in the generation of arousal and insomnia related to sleep deprivation-induced stress. It is difficult to conceive that chronic sleep deprivation in humans could be obtained and maintained without any activation in the stress axis. and very recently electrophysiological evidence has shown that neural discharge in the central amygdala is a consequence of repeated low-current.

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