Life Sciences 86 (2010) 1–9

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Corticotropin releasing factor and neuroplasticity in cocaine addiction
M. Corominas ⁎, C. Roncero, M. Casas
Department of Psychiatry, Vall d'Hebron University Hospital, Universitat Autonoma of Barcelona, Barcelona, Spain

a r t i c l e

i n f o

a b s t r a c t
Corticotropin releasing factor (CRF), one of the major effectors of stress, plays a major role in the natural course of drug addiction by accelerating the acquisition of psychostimulant self-administration and increasing incentive motivation for the drug itself and for drug-associated stimuli. Stress-induced CRF is also considered a predictor of relapse and is responsible for feelings of anxiety and distress during cocaine withdrawal. Despite this knowledge, the role of CRF has not been explored in the context of recent research on reward-related learning, built on the hypothesis that neuroplastic changes in the mesocorticolimbic circuitry underlie addiction. The present review explores the effects of stress on the pattern of interaction between CRF, dopamine and glutamate in distinct structures of the mesocorticolimbic circuitry, including the ventral tegmental area (VTA), amygdala, bed nucleus of stria terminalis (BNST) and the prefrontal cortex (PFC), after acute and chronic cocaine consumption as well as in early withdrawal and protracted abstinence. A better knowledge of the neurochemical and cellular mechanisms involved in these interactions would be useful to elucidate the role of CRF in cocaine-induced neuronal plasticity, which could be useful in developing new pharmacological strategies for the treatment of cocaine addiction. © 2009 Elsevier Inc. All rights reserved.

Article history: Received 1 April 2009 Accepted 2 September 2009 Keywords: Withdrawal Relapse CRF Stress Dopamine Glutamate Plasticity Neuropeptide

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroplasticity and CRF in cocaine addiction in the VTA . . . . . . . . . . . . CRF-related neuroplasticity in the extended amygdala . . . . . . . . . . . . . Short-term CRF-related plasticity in the BNST . . . . . . . . . . . . CRF-related plasticity in the CeA and BNST during abstinence . . . . Impact of CRF transmision in the prefrontal cortex . . . . . . . . . . . . . . . Could CRF antagonists prevent the addictive effects of cocaine and relapse during Could CRF antagonists prevent anxiety during cocaine withdrawal? . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . withdrawal? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 3 3 3 4 5 5 5 6 6

Introduction Addiction to psychostimulants is a chronic relapsing disorder characterized by an intense desire for consumption (craving) during withdrawal that leads to a progression from the initial impulsive consumption to subsequent compulsive consumption with loss of control over drug intake (Koob and Le Moal 1997; Robbins and Everitt
⁎ Corresponding author. Department of Psychiatry, Vall d'Hebron University Hospital, Edifici Escola d'Infermeria, 5ª planta, Pg, Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Tel.: +34 93 489 42 94/34 93 489 42 95; fax: +34 93 489 45 87. E-mail address: mcoromin@vhebron.net (M. Corominas). 0024-3205/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2009.11.005

1999; Robinson and Berridge 1993). Cocaine addiction has been hypothesized to be due to drug-induced neuroplastic changes in the mesocorticolimbic dopaminergic system and its interaction with glutamate (GLU) system, which underlie reward-related learning and memory processes (Everitt and Robbins 2005; Hyman and Malenka 2001; Nestler 1997). Addiction has also been described as a dysregulation of reward and hedonic processing contributing to symptoms of early and even protracted withdrawal (Koob and Le Moal 1997, 2001; Koob et al. 2004). Clinical evidence in humans (Gawin and Kleber 1986; McKay 1995; Wallace 1989) and experimental animal models (Covington and Miczek 2001; Deminiere et al. 1992; Goeders and Guerin 1994; Haney et al. 1995; Kosten et al. 2000;

NAc: Nucleus accumbens. footshock stress induced reinstatement. 2007. including the afferents from the BNST. amygdala. Thus the role of CRF in psychostimulant-induced neuroplasticity in the mesocorticolimbic system remains unexplored. 1990. 1987. although in lower levels than other brain regions (Sauvage and Steckler 2001). CRF-R2 has also been found in the VTA (Ungless et al. Additionally. Erb et al. 1993. Recently. 2003. Kalivas et al. GLU: Glutamate. 1). 2007. restructuring synaptic contacts. Piazza et al. The VTA expresses CRFR1. CRF activates two receptors. and facilitating relapse during abstinence (Erb et al. CRF: Corticotropin releasing factor. De Lima et al. In animals repeatedly treated with cocaine. Shaham et al. footshock stress increased DA and GLU levels in the VTA in cocaine- . Ramsey and Van Ree 1993) have demonstrated that stress plays a crucial role in drug addiction. the central nucleus of the amygdala (CeA). DA and GLU are also included. Kalivas et al. CP: Caudate-putamen. 2007). facilitates addiction by increasing locomotion (Cador et al. Elucidation of this role could be useful for developing pharmacotherapy for psychostimulant addiction. (2005) found evidence for the involvement of glutamatergic mechanisms in the CRF-induced activation of VTA DA neurons in response to stress. D2: D2 receptor. 2008) may enhance DA release in the projection areas. D1: D1 receptor. this knowledge has not been explored in the context of recent research on reward-related learning in psychostimulant addiction (Corominas-Roso et al. Castells et al. distributed throughout brain regions associated with the effects of drugs of abuse (Van Pett et al. CeA: Central nucleus of the amygdala. DA: Dopamine. Nestler 1997). “+”: Excitatory projections. (1987) conducted one of the first studies on the behavioral effects of CRF in the VTA. suggesting that GLU releasing neurons are also part of the neuronal circuitry mediating the effects of CRF in the VTA dopaminergic neurons (Tagliaferro and Morales 2008). Recent evidence has demonstrated that CRF acts as a central neurotransmitter (Swanson et al. 1997. NMDA: N-methyl-D-aspartate receptor.and long-term plasticity in the mesocorticolimbic circuits during cocaine consumption and abstinence. and the paraventricular nucleus of the hypothalamus (PVN) (Rodaros et al. Footshock was accompanied by an increase of CRF in the VTA in both cocaine-treated rats and cocaine-naïve animals. 1989. DA release from the VTA efferents plays a key role in drug seeking behavior (Phillips et al. CRF type 1 (CRF-R1) and CRF type 2 (CRF-R2) (Dautzenberg and Hauger 2002). Wang et al. 1993. Stewart 2000). Despite research supporting the role of CRF in drug addiction (Cador et al. but not the protein kinase A (PKA) pathway. CRF-R2: CRF type 2 receptor. Consistent with these results. Neuroplasticity and CRF in cocaine addiction in the VTA In the VTA. 2007. Recent studies have revealed that most synapses between CRFcontaining neurons and dopaminergic neurons in the VTA are asymmetric and mostly glutamatergic.2 M. 2007. Kalivas et al. 1986). GABA: Gamma-aminobutyric acid receptor. Sarnyai et al. Wanat et al. However. the potential utility of CRF receptor antagonists in preventing the development of cocaine addiction and relapse will also be explored. and some amygdaloid nuclei. (2008) reported that CRF was able to induce an increase in the firing rate of VTA DA neurons in a dose-dependent manner. 2003). Includes CRF-containing and CRF receptor-expressing nuclei in different structures of the mesocorticolimbic circuitry. Additionally. Weiss et al. 2000). The CRF-induced increase in the activity of the VTA DA neurons Fig. PFC: Prefrontal cortex. Hyman and Malenka 2001. whereas unpredictable stress increased both GluR1 and N-methyl-D-aspartate receptor (NMDAR1) expression in the VTA (Fitzgerald et al. CRF-R1: CRF type 1 receptor. Evidence from studies on the effects of stress in drug addiction show that repeated stress. In rats previously trained to self-administer cocaine and that had extinguished the cocaine seeking habit. mainly in the ventral tegmental area (VTA) (Rodaros et al. 1987). One of the major effectors of stress. the amygdala and bed nucleus of stria terminalis (BNST) (Erb and Stewart 1999. 1998. Corominas et al. 1992. mediating the response to conditioned stimuli (Lu et al. 2002). 1998. potentiating drug seeking behavior and the response to reward predicting stimuli. CRF has also been associated with anxiety in early cocaine withdrawal (Ambrosio et al. Chronic cocaine consumption and withdrawal induce long-term neuroplastic changes in this circuitry inducing a new allostatic state. BNST and the PFC. Swanson et al. can enhance strength at GLU excitatory synaptic transmission in the midbrain DA neurons (Saal et al. BNST: Bed nucleus of the stria terminalis. Knowledge of the neurochemical and cellular mechanisms of this interaction could shed light on the potential role of CRF in chronic cocaine-induced plasticity in the mesocorticolimbic system and on the contribution of CRF in the development of the emotional and behavioral changes that characterize addiction. 2003). 1996). 1983) (see Fig. repeated restraint stress increased levels of GLUR1 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptor subunit). 1983). Everitt and Robbins 2005. being expressed in areas of the mesocorticolimbic system. the behavioral effects of CRF appear to be mediated by complex mechanisms in the VTA. VTA: Ventral Tegmental Area. 2001) and the prefrontal cortex (PFC) (Lewis et al. 1992. This review examines recent research on the role of CRF and its interaction with dopamine (DA) and GLU in drug-induced mechanisms of short. suggesting their interaction with the CRF system. 2001. corticotropin releasing factor (CRF). will be examined. nucleus accumbens (NAc). Lodge and Grace (2005) reported that both acute and chronic blockade of the CRF-R1 attenuated cocaine-induced DA release in the NAc. Basic circuitry expressing the effects of corticotrophin releasing factor (CRF) in cocaine addiction and withdrawal. as well as chronic cocaine treatment. Rodaros et al. (Wanat et al. 1998). an effect that was not blocked by pretreatment with the DA receptor antagonist haloperidol. 1. 1995). / Life Sciences 86 (2010) 1–9 Miczek and Mutschler 1996. There is also evidence that repeated stress is able to upregulate GLU receptors in the VTA. In a series of experiments. These are mechanisms through which stress can induce long-term neuroplastic changes in the VTA. even though CRF-R2 mRNA had been reported to be absent from the VTA (Van Pett et al. This effect was mediated by CRF-R1 through activation of the phospholipase C (PLC)-protein kinase C (PKC) signaling pathway. 2003). Lu et al. 1997. 2001). structures of the mesocorticolimbic circuitry where CRF and its receptors are mainly expressed. AMPA: Alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor. CRF arises from multiple sources. Shaham et al. 2000). which is currently lacking (Cami and Farre 2003. More specifically. BLA: Basolateral nucleus of the amygdala. The VTA. Millan et al. including the PFC. CRF injection in the VTA dosedependently increased locomotion in rats.

anxiety. (2007). these results suggest that chronic cocaine consumption induces long-lasting neuroplastic changes in the VTA that are partly dependent on CRF release and involve GLU and DA neurons. The use of a non-specific CRF receptor (CRF-R1 and CRF-R2) antagonist prevented the enhancement of DA and GLU. extracellular levels of CRF increased in the CeA (Richter and Weiss 1999). suggesting that in the VTA CRF does not directly act on DA neurons. the effects of CRF were predominantly mediated by CRF-R2 linked to PKC pathway. The involvement of VTA CRF-R1 is also in agreement with studies reporting a decrease of DA release in the NAc and VTA after the use of CRF-R1 antagonists in rats previously trained in a place preference paradigm (Lu et al. 2008). 2007). (2008) shows a mechanism requiring interaction between DA and CRF to activate excitatory transmission. (2009) in the VTA. The new recruitment of CRF-R1 and PKA (Hahn et al. Pollandt et al. in slices obtained after long-term cocaine withdrawal. but only after repeated cocaine exposure. The excitatory inputs to the VTA are mediated through NMDA and non-NMDA receptors (Georges and Aston-Jones 2001. The CRF-related LTP was enhanced in cocaine-treated rats 2 weeks after withdrawal.and D2-like receptors rapidly enhances glutamate excitatory transmission. 1992. (2006) reported that CRF enhanced long-term potentiation (LTP). in vivo acute cocaine administration induced a DA signaling and CRF-Rdependent enhancement of NMDA excitatory transmission. Finally. 2006) contrasts with the findings of Wang et al. In agreement with previous studies (Ungless et al. The delayed changes in the CRF system during withdrawal suggest the involvement of this neuropeptide in persistent modification of neuronal activity in these amygdaloid nuclei. Systemic administration of the CRF-R2 antagonist was not reported. CRF-related neuroplasticity in the extended amygdala The extended amygdala. 2001). Recent evidence suggests a central role for BNST CRF in the acute effects of drugs of abuse (Kash et al. In animal models. 2008). 2000. enhanced CRF levels persisted in the amygdala 6 weeks after cocaine cessation (Zorrilla et al. but not 24 h after withdrawal. In humans. but not CRF-R1. This increase in CRF levels coincides with the time of behavioral anxiety in rats during withdrawal (Sarnyai et al. suggesting that CRF acquired control over VTA GLU and DA release. the increased response to CRF was accompanied by enhanced GLU transmission and NMDAR function (Pollandt et al. 2004) and the decrease of hedonic responses during abstinence (Harris and Aston-Jones 2007). During early withdrawal in cocaine self-administering rats. the initial enhancement of NMDAR function in cocaine-treated animals was mediated through CRF-R1 and PKA. After 5 days of intraperitoneal cocaine injections. (2007) used HFS in the neural afferents connecting the . 2009) is in accordance with other studies reporting the same signaling mechanisms underlying chronic cocaine effects in the amygdala (Pollandt et al. Maren and Fanselow 1995). in this study. 2006). The increase of LTP relied on functional changes in CRF receptors and intracellular signaling mechanisms. Epping-Jordan et al. Enhanced CRF levels have also been reported in the BNST in rats self-administering ethanol after withdrawal (Olive et al. Wanat et al. These results. Together. as well as in footshock-induced reinstatement of cocaine seeking (Wang et al. and the BNST also expresses high density of CRF receptors. and in decreased interest for natural rewards during abstinence (Harris and Aston-Jones 2007). Rodaros et al. 2002). Experimental evidence suggests that CRF mediates synaptic plasticity in the CeA during protracted withdrawal. Both the CeA and the BNST have abundant CRF-containing cells (Rainnie et al. these effects were dependent primarily on an enhanced activity of CRF-R1 and PKA. anhedonia and depression lasting several hours to days after withdrawal (Gawin and Kleber 1986). 2009. Whereas in saline-treated slices. 2009). 2005). Erb et al. Corominas et al. which play a role in stressinduced relapse (Wang et al. a new mechanism recruited by CRF only after repeated cocaine consumption. activated in the VTA only in animals previously exposed to repeated cocaine. McFarland et al. perfused locally into the VTA.M. the CRF-induced activation of glutamatergic transmission was mediated through CRF-R2 and PKC (Hahn et al. Additionally. the BNST robustly innervates the VTA and has a potent excitatory influence on DA neuron firing. the interaction between DA and CRF systems in the BNST can enhance the acute effects of drugs of abuse (Kash et al. a shortterm form of plasticity (STP) in the BNST (Kash et al. DA release acting through D1. during long-term cocaine withdrawal. Additionally. aSvg-30. Additionally. CRF also induced a potentiation of AMPA receptor (AMPAR)-mediated transmission. CRF-R1 and CRF-R2 (Chalmers et al. Short-term CRF-related plasticity in the BNST The BNST is a limbic structure profusely innervated by DA fibers (Fudge and Emiliano 2003) that has been implicated in the reinforcing effects of cocaine (Carboni et al. 2002). perfusion of a GLU antagonist in the VTA prevented both cocaine reinstatement and DA release but not the increase of GLU levels. 2003. The reported role for CRF-R1 and PKA (Hahn et al. a measure of the strength of synaptic contacts. cocaine abstinence is characterized by irritability. 2004). in the increasing GLU release and DA neuron firing. these results were found with the selective CRF-R2 antagonist. especially during withdrawal. 2003). Nevertheless. in the neural pathway which projects from the lateral amygdala to the CeA (LA-CeA pathway). A recent study by Hahn et al. CRF-related plasticity in the CeA and BNST during abstinence The BNST plays a prominent role in stress-induced reinstatement during cocaine withdrawal (Erb and Stewart 1999. / Life Sciences 86 (2010) 1–9 3 trained but not in cocaine-naïve animals. 2008). which includes the CeA and the BNST. 1995). acting on glutamatergic terminals. and would have important behavioral consequences even in the long term. Together. Fu et al. reported in the CeA during protracted cocaine abstinence. The sustained enhancement of NMDAR function induced by CRF after repeated cocaine exposure required activation of both CRF-R1 and CRF-R2. CRF induced a sustained enhancement of VTA NMDA receptor (NMDAR)-mediated excitatory transmission compared with naïve and saline-treated animals. 2002). suggesting an additional neurochemical mechanism. 1995). these results suggest that chronic cocaine use and subsequent withdrawal induces long-lasting neuroadaptations in the VTA. The CeA has also been involved in both the effects of stress in reinstatement (McFarland et al. is a major source of extrahypothalamic CRF-containing neurons and expresses both CRF-R1 and CRF-R2 receptors. 2007). in naïve or saline-treated animals. 2001. are in agreement with those reported by Hahn et al. high-frequency stimulation (HFS) of neuronal bundles induces enduring changes in synaptic contacts (LTP) (Akirav and Richter-Levin 1999. 2008). being present both during early and late withdrawal. This dopaminergic effect is activity-dependent and requires endogenous CRF release and recruitment of CRF-R1 signaling (Kash et al. the study by Kash et al. 2008). In this limbic region. Bearing in mind the potent excitatory influence on VTA DA neurons (Georges and Aston-Jones 2001. In this study. 2006). 1998) (see Fig. as well as both PKC and PKA. Unlike reports indicating that CRF can regulate the activity of VTA DA neurons through glutamatergic mechanisms (Ungless et al. 2003). These authors found the involvement of CRF-BP and CRF-R2 in the VTA. In different amygdalar synapses. the effect of CRF on GLU and DA release in the VTA was long lasting. 1). In its turn. This would change responses to reward and reward predicting stimuli. (2009) provides evidence on the mechanisms by which chronic cocaine enhances CRF potentiation of glutamate transmission in VTA DA neurons. Pollandt et al.

2009. Lewis et al. an effect that depends on the territory of the PFC (McFarland et al. 2009). Carmichael and Price 1995) and. such as those associated with drug consumption. 2006). 1989. would be able to activate and guide behavior. However. 1996) in response to drug-associated stimuli leading to relapse. HFS enhanced LTP in the BLA-CeA terminals after long-term withdrawal. Pascucci et al. In humans. 2007. 2008). In the context of cocaine addiction. 2001. which may have profound consequences in addicts. Synaptic restructuring in the BLA-CeA fibers during long-term withdrawal (Fu et al. Long-term potentiation of intrinsic excitability (LTP-IE). after repeated cocaine administration in rats. Hayes et al. an effect that was not seen in control rats. Imperato et al. Together these studies suggest that during protracted withdrawal the increased activity of the CRF system mediates abnormal neuroplasticity. 1985. The consequences of the neuroplastic changes reported below in the CeA and the BNST. This study also reported impaired jcBNST LTP-IE in rats during protracted withdrawal after escalated cocaine self-administration. In the PFC. 2004. in drug-naïve rats. Additionally. Seamans and Yang 2004). BNST. can be understood considering the pattern of connectivity and functional properties of these neural structures. the BLA integrates information from the environment through its connections with the prefrontal cortex and hippocampus (Aggleton 1986. Impairment of LTP-IE in the jcBNST during protracted withdrawal may lead to a deficit of the functional properties of the BNST circuitry with a decrease of inhibitory influence on the CeA (Francesconi et al. The CeA plays a role by orchestrating autonomic and endocrine responses and is a major output nucleus of the amygdala (Fudge and Emiliano 2003). Previous studies reported that repeated cocaine administration induced a change in the functional properties of the D1 receptors in the PFC. 1). 1). 1986). whereas the G protein activity coupled to D2 was reduced following cocaine withdrawal (Bowers et al. even long after drug cessation. 2007). Together. These results suggest that chronic activation of the CRF system can contribute to abnormal long-term neuroplastic changes in the BNST. Impact of CRF transmision in the prefrontal cortex CRF and its receptors are widely distributed in the PFC (Grammatopoulos et al. are also important components of PFC connectivity (see Fig. 1). Gresch et al. Kash and Winder 2006). which modify the integration properties of the CeA and BNST. (2008) found evidence for a new interaction between CRF and DA on GLU transmission in the PFC after chronic cocaine. has an inhibitory effect on PFC function by modulating the activity in this cortical region (Mair and Kauer 2006. These results are in agreement with those published by other authors (Pollandt et al. The BNST is also anatomically well situated to receive emotional and learning-associated information and to integrate it with reward and motivation (Jalabert et al. BNST and other limbic structures. Additionally. a protracted increase in the probability of firing and/or efficacy of neuronal circuits (Desai et al. Fuchs et al. Deutch et al. channels information to the CeA. the change in the integration properties of the BNST during abstinence could have profound consequences on the excitatory influence of the BNST on VTA DA neuron firing and on the response of the DA system to rewards. an effect requiring the activation of NMDA GLU receptors and N-type voltage-gated calcium channels (Fu et al. These neuronal changes may underlie the feelings of anxiety and distress that lead to relapse during early withdrawal and protracted abstinence (Francesconi et al. impairing the functional properties of this structure. in turn. Matuszewich et al. This impairment was also induced after repeated alcohol and heroin exposure in the same brain region. the synergistic effects of CRF and DA in the PFC changed . The BNST projects to the CeA and to other limbic nuclei involved in drug abuse including the basolateral nucleus of the amygdala (BLA) and the Nac-core (see Fig. 2003. but not shortly after cocaine cessation. In control saline-treated rats. 2001. Limbic structures. 2001. (2005) suggested that enhanced D1 activity would lead to an increased inhibitory state of the PFC during withdrawal. 1994). 1999. the stress-induced increase in DA transmission is transient and rapidly returns to baseline levels (Abercrombie et al. which may cause increased anxiety and distress during abstinence. further leading to reinstatement. Repeated stress can also modify the sensitivity of DA D1 receptors in the medial PFC (mPFC). coupled to D1 receptors. Sorg et al. 2009). modulating excitatory synaptic transmission and activity of pyramidal neurons in these cortical regions (Floresco and Tse 2007. Grant et al. even after long-term abstinence. However. Recent evidence has also implicated the BNST in CRF-dependent long-term neuroplasticity (Francesconi et al. may potentiate the emotional effects of drug-conditioned stimuli. Koob et al. Kalivas et al. 2006) and suggest a role for CRF in encoding cocaine withdrawal related information in the CeA synapses. and a generalized hedonic deficit that lead to relapse. has been demonstrated in the juxtacapsular-BNST (jcBNST) (Francesconi et al. the CRF system enhances memory consolidation (Roozendaal et al. CRF induced activation of synaptic transmission in the BLA-mPFC. CRF acting through postsynaptic CRF-R1 enhanced the inhibitory effects of DA on excitatory transmission in the BLA-mPFC projections. 2004. In addition. Paspalas and Goldman-Rakic 2004). NAc and striatum. including restructuring synaptic contacts and changing neuronal excitability. 1989. induced disturbances of LTP-IE similar to those induced during protracted withdrawal. Recently. the BLA is known to play a crucial role by mediating the effect of cocaine-conditioned stimuli. 2004). both the CeA and BNST can play a role in integrating sensory information (Harris and Aston-Jones 2007). had no effect. Carelli et al. 2009). / Life Sciences 86 (2010) 1–9 basolateral amygdala (BLA) and the CeA (BLA-CeA pathway) to simulate cue-stimuli. 2002. This change was attributed to an enhancement of the activity of the G protein signaling 3 (AGS3). Parkinson et al. Kreek and Koob 1998). repeated but not acute administration of CRF in the jcBNST. In the BLA. 2009). In other words. 2006. associated to cocaine consumption. LTP is a well-established basic model of the cellular processes that lead to the formation of new synapses and remodeling of existing ones. Turrigiano et al. 1989. 2007). the increase in CRF activity appeared to modify the modulatory effects of DA on excitatory GLU transmsision in the mPFC. It is known that DA. According to this pattern of connectivity. CRF-R1 mediated the enhancement of synaptic strength during withdrawal. Disturbances of jcBNST LTP-IE were associated with chronic activation of CRF signaling and were prevented by administration of the selective CRF-R1 antagonist R121919. The selective CRF-R2 antagonist. 2009). Pollandt et al. dopaminergic activity is increased in response to different kinds of stressors in animal models (Abercrombie et al. acting through D1/5 receptors. Dopaminergic afferents from the VTA project to widespread subregions of the PFC. so that only particularly strong stimuli. 1994). Hall et al. 2004) and on individual vulnerability to the effects of stress (Sorg et al. Orozco-Cabal et al. Corominas et al. In animals previously treated with intermittent repeated cocaine. These results suggest a role for CRF in restructuring synaptic contacts in the CeA during cocaine abstinence. which contributes to reinstatement in cocaine seeking during withdrawal (Cardinal et al. these results support the view of addiction as an allostatic state with predominant feelings of anxiety and distress. 2002. astressin2-B. 1999). 1999. Millan et al. the amygdala and related structures are part of the neural circuitry activated during cocaine craving (Childress et al.4 M. including the amygdala. During early withdrawal. 2003. such the NAc-core (see Fig. together with long-term changes in the excitatory properties of the BNST (Francesconi et al. 1989. underlying information storage within the neural systems (Geinisman 2000). 2004). even after long-term abstinence (Koob and Le Moal 1997. The efficacy of neuronal circuits can be modified not only by changing the strength of synaptic contacts but also by modifying intrinsic neuronal excitability.

2003). 2003). 2005). In the PFC. was . This enhanced CRF function potentiates longterm neuroplasticity. due to repeated cocaine consumption and withdrawal. behavioral anxiety can be measured using different paradigms.526. and in anticipating the future consequences of actions (Bechara et al. In this context. was able to prevent cocaine-induced reinstatement after 28 days of withdrawal (Lu et al. CRF-related synaptic plasticity in the VTA can have crucial consequences in the pattern of DA release in the projection areas. particularly in the VTA. the use of CRF-R1 antagonists had no effect in reducing reinstatement (Wang et al. On one hand. facilitating activity in the BLA afferents to the mPFC (Orozco-Cabal et al. such as the BNST or the VTA. intracerebroventricular CP-125. CP-125. without modifying food-responding.and long-term withdrawal potentiate drug-induced neuroplasticity. In a model of CPP. Sun et al. such as the defensive burying paradigm (Harris and Aston-Jones 1993) or the elevated plus maze (Pellow et al. 2005). The increase in rewarding effects is due to the role of CRF in the VTA. produced a dose-related decrease in cocaine self-administration. Intraperitoneal pretreatment with the selective CRF-R1 antagonist. such as the NAc. but not the specific CRF-R2 antagonist. CP-154. 2008). CRF receptor antagonists have been reported to be useful in preventing reinstatement in cocaine seeking after withdrawal (see Table 1). For example. In rats previously trained to self-administer cocaine. In the PFC. CP-154. In the same brainstem region. may account for maladaptive synaptic plasticity in this structure. blocked footshock-induced reinstatement in abstinent rats previously trained to self-administer cocaine. suggesting that systemic selective CRF-R1 antagonists can be useful in preventing stress-induced relapse to cocaine use. Corominas et al. the increased CRF levels during short. 1994. Could CRF antagonists prevent anxiety during cocaine withdrawal? Experimental studies have reported that the use of CRF receptor antagonists can be useful in preventing behavioral anxiety related to cocaine withdrawal in animal models (see Table 1). the possible use of selective CRF-R2 antagonists has also been tested. Conversely. addicts have difficulties in adapting behavior to new environmental contingencies. Interestingly. administration of CP-154. This change in the functionality of CRF receptors was consistent with results reported in the lateral septum (Liu et al. a process known as reversal learning (Kringelbach and Rolls 2003). In this study. 2008). treatment with the selective antagonists reduced cocaine intake in animals with extended access to cocaine (Specio et al. 2006). In these models. Interestingly. but not the selective R1 or R2 antagonist. CRF is also involved in abnormal patterns of synaptic plasticity in the CeA and in long-term changes of the intrinsic neuronal excitability in the BNST. 2006. 1999. These results suggest a decrease of cocaine reinforcement effects induced by CRF-R1 antagonist (Goeders and Guerin 2000). Systemic administration of CRF receptor antagonists has also been found to be useful in preventing stress-induced reinstatement during withdrawal in cocaine treated rats (see Table 1). Since the VTA has been involved in stressinduced relapse of cocaine seeking (Wang et al. / Life Sciences 86 (2010) 1–9 5 to excitatory. 2004). through glutamatergic mechanisms in the VTA. Conclusions CRF acts in distinct structures of the mesocorticolimbic circuitry with repeated cocaine consumption. but persists during protracted abstinence. 2007. partly mediated by excitatory projections from the BNST. (1999) reported the anxiolytic-like effect of the CRF receptor antagonist. On the other hand. both having profound consequences on the integrative properties of these neural structures. the switch in the synergistic effects of CRF in the mPFC after cocaine withdrawal was mediated through CRF-R2 activation with a loss of function of CRF-R1 receptors (Orozco-Cabal et al. a process that underlies learning in the normal brain (Matsuda et al. antalarnin and MPZP. 2007). which leads to relapse.526.526 in the absence of footshock had no effect on extinguished drug seeking (Shaham et al. The use of CRF receptor antagonists has also been reported to be useful in reducing the reinforcing effects of cocaine in animal models (see Table 1). Pretreatment with the selective CRF-R1 antagonist. only the non-specific α-helical CRF antagonist. The increase in CRF function induced by chronic cocaine treatment during withdrawal in the mesocorticolimbic circuitry is not transient. Gawin 1991. the exact nature of the changes in the PFC is still not well understood. footshock-induced reinstatement was prevented by selective VTA CRF-R2 blockade (Wang et al. AS-30. these antagonists had no effect on baseline extracellular DA levels (Lu et al. also found to prevent conditioned reinstatement in rats chronically treated with cocaine (Goeders and Clampitt 2002) (see Table 1). non-specific CRF receptor antagonists were able to prevent contextual cue-induced anxiety in rats previously treated with cocaine (De Vries and Pert 1998). D-phe CRF(12–41). After cocaine self-administration behavior was acquired. 1992. 2005) and appears to express CRF-R2 receptors (Ungless et al. CeA and BNST. had no effect. CRF has a biphasic role. had a significant inhibitory effect on cocaine-induced place preference (Lu et al. During withdrawal. Basso et al. Equivalent results were reported for two different selective CRF-R1 antagonists. whereas the specific CRF-R2 antagonist. BNST and the PFC. Pretreatment with the selective CRF-R1 non-peptide antagonist. the increased CRF response induced by repeated cocaine consumption and withdrawal induces a change in the functional properties of this structure.526. 1985). Avoiding the increase in CRF levels using an immunoserum against CRF completely prevented the development of anxiety induced by cocaine withdrawal (Sarnyai et al.526 and the non-specific α-helical CRF antagonist.M. especially cues associated with cocaine consumption (Goldstein et al. CRF enhances the acute effects of drugs of abuse. CRF-related plasticity during chronic cocaine consumption and withdrawal can have important emotional and Could CRF antagonists prevent the addictive effects of cocaine and relapse during withdrawal? When administrated to the central nervous system or directly into specific brain nuclei. Most of these deficits are included in what has been conceptualized as executive functions (Goldstein et al. which engage mechanisms of synaptic plasticity. Importantly. attenuated footshock-induced reinstatement. Abnormal engagement of the mechanisms of synaptic plasticity in the PFC during changes in DA release. D-Phe CRF12–41. Moreover. alterations in CRF mechanisms during cocaine withdrawal would contribute to abnormalities in synaptic plasticity in the PFC. O'Brien et al. the extended amygdala – including the CeA and BNST – and the PFC. 2003). in processing emotional information. The chronic relapsing course of cocaine addiction may be induced by exposure to environmental cues previously associated with cocaine (Ehrman et al. 1998). Intracerebroventricular (Erb et al. DA facilitates induction of LTP through glutamatergic mechanisms by AMPA receptor synaptic insertion. in rats previously treated with cocaine injected intraperitoneally for 14 consecutive days. Overall. De Martino et al. The same CRF-R1 antagonist can also block stress-induced reinstatement after long-term withdrawal (28 days of extinction) in a cocaine-conditioned place preference. 2001. Kalivas and Volkow 2005). However. 1995). CP-154. 1992). 2001). 2007). 2008). amygdala.526 and α-helical administration reduced the effect of cocaine on extracellular DA levels in Nac and VTA. leading to the behavioral deficits that characterize addiction. greater knowledge of CRF would be useful for finding new pharmacological strategies for the treatment of cocaine addiction. 1998) and intra-BNST (Erb and Stewart 1999) administration of the CRF receptor antagonist.

1986. Corominas et al. In agreement with the neurochemical mechanisms of CRF and based on scientific results. that lead to relapse during early withdrawal and protracted abstinence. Synapse 25 (3). Experimental Brain Research 64 (3). (2001) Lu et al. and medial frontal cortex. the use of both selective and nonselective CRF-R1 antagonists can be useful in reducing cocaine consumption. (2005) Wang et al. The Journal of Neuroscience 19 (23).526 Selective CRF-R1: CP-154. (1999) De Vries and Pert (1998) Sarnyai et al. R2) to prevent chronic cocaine effects. Aggleton JP.526 α-helical (non-selective) Selective CRF-R2: AS-30 α-helical (non-selective) Selective CRF-R1: CP-154. (1998) Erb et al. 1655–1658. (2001) Basso et al. Although there is less evidence for the utility of the CRF-R2 receptor antagonist in preventing reinstatement in cocaine seeking. 10530–10535.526 Selective CRF-R2: AS-30 D-Phe CRF(12–41) α-helical (non-selective) CRF-antiserum Preventing behavioral effects Yes Yes Yes Yes Yes Yes Yes Yes Yes Modulatory effect Yes Yes No Yes Yes No Yes No No Yes Yes Yes Reference Goeders and Guerin (2000) Goeders and Clampitt (2002) Specio et al. 1999. This change in the signaling mechanisms is reported both in the VTA and the CeA. (2001) Lu et al. The authors are grateful to Ira Potashner Ph.D. (2003) Lu et al.526 D-Phe CRF12–41 (non-selective) D-Phe CRF12–41 (non-selective) Selective CRF-R1: CP-154. even in response to cocaine-conditioned stimuli. Differential effect of stress on in vivo dopamine release in striatum. (2003) Lu et al. Basso AM. behavioral consequences. which switch from activation of CRF-R2 and PKC to being primarily mediated through CRF-R1 and PKA. and in preventing the feelings of anxiety and distress and subsequent relapse during withdrawal. (2001) Lu et al. Chronic cocaine treatment is able to induce a change in CRFsignaling mechanisms. (2008) Specio et al. Vale W. / Life Sciences 86 (2010) 1–9 Table 1 Studies on the use of CRF receptors (R1. psychologist. (1998) Lu et al. the use of these antagonists should be studied in depth to determine its possible utility in preventing aberrant neuroplasticity in the VTA and the PFC. (2008) Wang et al. (2001) Lu et al. A description of the amygdalo-hippocampal interconnections in the macaque monkey. (2003) Lu et al. Keefe KA. Rivier J. (2001) Lu et al. DiFrischia DS. Ambrosio E. Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. the use of combined pharmacological strategies involving all these neurotransmitters should be considered. for providing writing assistance on this manuscript. Akirav I. considering the interactions among CRF. Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat.6 M. 272–276. Spina M. Richter-Levin G. 21–30. Acknowledgements This work has been supported by the Psychiatry Department of Vall d'Hebron University Hospital. 1999. Moreover.526 Selective CRF-R1: antalarnin Selective CRF-R1: MPZP α-helical (nonselective) Selective CRF-R2: antisauvagine-30 D-Phe CRF12–41 (non-selective) Selective CRF-R1: CP-154. Journal of Neurochemistry 52 (5). (1995) CRF-R1/CRF-R2 CRF-R1 CRF-R1/CRF-R2 CRF-R1 Elevated plus maze b Elevated plus mazeb a b Cocaine withdrawal Cocaine-context during withdrawal Cocaine withdrawal CRF-R1/CRF-R2 CRF-R1/ CRF-R2 Model of chronic cocaine intake. (2007) Erb and Stewart (1999) Shaham et al. Psychopharmacology 145 (1). 1997. . Model of behavioral anxiety. (1998) Erb et al. Pilotte NS. 1989. GLU and DA in the different structures of the mesocorticolimbic system. nucleus accumbens. Sharpe LG. Bearing in mind the functional significance of the PFC.526 Selective CRF-R2: AS-30 α-helical (nonselective) Selective CRF-R1: CP-154. Regional binding to corticotropin releasing factor receptors in brain of rats exposed to chronic cocaine and cocaine withdrawal. Zigmond MJ. Koob GF. References Abercrombie ED. a better understanding of the involvement of CRF in this structure would aid the development of new strategies for restoring PFC function. Models Self-administrationa Behavior inductor Cocaine Cocaineconditioned cues None None Stress Stress Stress Stress Stress Cocaine Place preferencea Cocaine Cocaine Cocaine Stress Stress Stress Cocaine Cocaine Cocaine Defensive burying b Effect prevented CRF receptor or reduced involved Responding on cocaine lever Reinstatement Cocaine intake Cocaine intake Reinstatement Reinstatement Reinstatement Reinstatement Reinstatement Reinstatement Place preference conditioning Place preference conditioning Place preference conditioning Place preference reactivation Place preference reactivation Place preference reactivation Place preference reactivation Place preference reactivation Place preference reactivation Burying latency Open arm exploration Time spent in open arms CRF-R1 CRF-R1 CRF-R1 CRF-R1 CRF-R2/CRF-R1 CRF-R2 CRF-R1 CRF-R1 CRF-R2/ CRF-R1 CRF-R2/ CRF-R1 CRF-R1 CRF-R2/ CRF-R1 Dosage schedule Single dose (prior to selfadministration) Single dose (prior test for reinstatement) Single dose (following escalation period) Single dose (following escalation period) Single dose (prior stressinduced reinstatement) Single dose (prior stressinduced reinstatement) Single dose (prior stressinduced reinstatement) Single dose (prior stressinduced reinstatement) Single infusion (prior stressinduced reinstatement) Single infusion (prior stressinduced reinstatement) Single dose (prior to each injection of cocaine) Single dose (prior to each injection of cocaine) Single dose (prior to each injection of cocaine) Single dose (prior to test situation) Single dose (prior to test situation) Single does (prior to test situation) Single dose (prior to test situation) Single dose (prior to test situation) Single dose (prior to test situation) Single dose (prior to test situation) Single dose (prior to test situation) Single dose (prior to each injection of cocaine) CRF antagonist Selective CRF-R1: CP-154. 515–526.

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