Role of amygdala in drug memory

Neurobiology of Learning and Memory xxx (2013) xxx–xxx

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Role of amygdala in drug memory Yi-Xiao Luo, Yan-Xue Xue, Hao-Wei Shen, Lin Lu ⇑ National Institute on Drug Dependence, Peking University, Beijing 100191, China

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Article history: Available online xxxx Keywords: Addiction Relapse Amygdala Drug memory

a b s t r a c t Drug addiction is a chronic brain disorder with the hallmark of a high rate of relapse to compulsive drug seeking and drug taking even after long-term abstinence. Addiction has been considered as an aberrant memory that has been termed ‘‘addiction memory.’’ Drug-related memory plays a critical role in the maintenance of learned addictive behaviors and emergence of relapse. Disrupting these long-lasting memories by administering amnestic agents or other manipulations during specific phases of drug memory is a promising strategy for relapse prevention. Recent studies on the processes of drug addiction and relapse have demonstrated that the amygdala is involved in associative drug addiction learning processes. In this review, we focus on preclinical studies that used conditioned place preference and selfadministration models to investigate the differential roles of the amygdala in each phase of drug-related memory, including acquisition, consolidation, retrieval, reconsolidation, and extinction. These studies indicate that the amygdala plays a critical role in both cue-associative learning and the expression of cue-induced relapse to drug-seeking behavior. Ó 2013 Elsevier Inc. All rights reserved.

1. Introduction Addiction is defined as a loss of control over drug use and obsessive drug seeking despite predictable adversity. It is characterized by compulsive drug-taking behavior and high rates of relapse to drug use even after prolonged abstinence from drug taking (Childress et al., 1999; Grant et al., 1996; Kilts et al., 2001). Although numerous studies have been conducted in the past several decades, the neural mechanisms that underlie drug addiction remain unclear, and no effective medications exist to cure drug addiction (Kalivas & Volkow, 2005). Many studies have convincingly supported the hypothesis that addiction usurps normal neural processes that underlie learning and memory. The formation of long-term drug-related associative memory contributes to persistent drug use and relapse to compulsive drug seeking when abstinent human addicts or animals are reexposed to previously drug-paired cues (Hellemans, Everitt, & Lee, 2006; Nestler, 2001; Robbins, Ersche, & Everitt, 2008). The term ‘‘memory of addiction’’ was first used by Mello in 1972. It was soon recognized as a comprehensive concept within the ‘‘reinstatement’’ framework, with implications for the entire addiction syndrome (Edwards & Gross, 1976). Emphasis on the process of conditioned learning has deepened our understanding of the important role of learned experiences in the development and maintenance of addictive behaviors, which has been demonstrated in both preclinical and clinical research (O’Brien, Childress, McLellan, ⇑ Corresponding author. Fax: +86 10 62032624. E-mail address: [email protected] (L. Lu).

& Ehrman, 1992). In human addicts, addiction syndromes that comprise compulsive drug taking and seeking may be controlled by learned conditioned associations between the intense reinforcing effects of repeated drug use and drug-paired cues. Investigations of the neural mechanisms that underlie conditioned associations are helpful to understand their role in relapse and its prevention (O’Brien, Childress, Ehrman, & Robbins, 1998). Accumulating evidence indicates that addiction is a pathological emotional memory-related disease because of the overwhelmingly intense associations between addictive behaviors and the social context where drug use behavior occurs. This has been supported by evidence that addicts are prone to recurrent drug craving and drug use when they are exposed to previously conditioned cues that predict the reinforcing effects of abused drugs (Leshner, 1997). The formation of drug-related memory results from repeated drug intake and may control persistent addictive behavior that consists of unmanageable loss of control for drug use and compulsive craving (Heyne, May, Goll, & Wolffgramm, 2000; Wolffgramm & Heyne, 1995). Therefore, revolutionizing our understanding of the nature of addiction and addiction memory can improve treatment strategies for addicts. Behavioral therapy methods, such as ‘‘cue-exposure therapy,’’ have been based on this progression of our understanding of drug addiction (Flor, Knost, & Birbaumer, 1997; Szegedi et al., 2000). However, drug-related memory stubbornly persists, and behavioral therapy methods cannot suppress its expression or modify the original drug-related memory (Boening et al., 2001). The amygdala is primarily considered as a brain center that controls emotional responses, supported mainly by several studies that used fear conditioning paradigms (LeDoux, 2000; LeDoux,

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Please cite this article in press as: Luo, Y.-X., et al. Role of amygdala in drug memory. Neurobiology of Learning and Memory (2013), http://dx.doi.org/ 10.1016/j.nlm.2013.06.017

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2003; Pare, Quirk, & Ledoux, 2004). From the perspective of anatomical structures, the amygdala has intricate bidirectional connections with the prefrontal cortex (PFC) that are more elaborated in human and nonhuman primates than in rodents (Ghashghaei & Barbas, 2002; Ghashghaei, Hilgetag, & Barbas, 2007; Wise, 2008). Complicated bidirectional projections also exist between higher sensory areas and single sensory areas and the amygdala (Amaral, 2003). The amygdala also projects nerve fibers to the mesolimbic system (Brog, Salyapongse, Deutch, & Zahm, 1993; Groenewegen, Berendse, Wolters, & Lohman, 1990), such as the nucleus accumbens (NAc), which has been shown by functional magnetic resonance imaging (fMRI) studies to be activated when craving occurs in cocaine addicts (Bonson et al., 2002; Breiter et al., 1997; Childress et al., 1999). The amygdala is considered as the primary region for encoding both aversive (LeDoux, 2003) and appetitive (Everitt, Cardinal, Parkinson, & Robbins, 2003) conditioned stimulus information in conditioned learning. When addicts are exposed to drug-related stimuli, including drug paraphernalia and cues, even after a prolonged period of drug abstinence, drug craving is intensely elicited, resulting in relapse to drug intake (Dackis & O’Brien, 2001; Gawin, 1991). Laboratory animal studies have demonstrated that the amygdala is crucial for conditioned drug seeking. The basolateral amygdala (BLA) plays a critical role in the formation of cocaine-induced conditioned place preference (Fuchs, Weber, Rice, & Neisewander, 2002). The indispensable role of the BLA is also revealed in another animal model, cocaine self-administration, using a second-order schedule of reinforcement (Everitt, Morris, O’Brien, & Robbins, 1991; Kantak, Black, Valencia, Green-Jordan, & Eichenbaum, 2002; Whitelaw, Markou, Robbins, & Everitt, 1996). Additionally, the central nucleus of the amygdala (CeA) has been shown to be required for the acquisition and expression of morphine-induced CPP (Rezayof, Zarrindast, Sahraei, & Haeri-Rohani, 2002; Zarrindast et al., 2004) and the incubation of drug craving (Li et al., 2008; Lu et al., 2005). The role of the amygdala in drug addiction has been well reviewed (Bernardi, Ryabinin, Berger, & Lattal, 2009; Koob, 2009). Given that drug-related memory has important implications in drug addiction and relapse and that the amygdala plays an indispensable role in encoding conditioned drug-related information, the present review focuses on studies that the amygdala plays different roles in various phases of drug-related memory using self-administration and CPP animal models. The characteristics and functions of the self-administration and CPP procedures have been discussed in detail in previous reviews (Lu, Shepard, Hall, & Shaham, 2003). The subjective reinforcing effects produced by drugs serve as unconditioned stimuli in the self-administration procedure. In the CPP procedure, reinforcement is produced by passively received drugs, and the drug-paired context or cues serve as conditioned stimuli. The association between drug reinforcement in the training procedure and the drug-paired context or cues can be established by repeated training sessions. After the conditioned response to unconditioned stimuli is established, such acquired behaviors can be extinguished by repeated exposure to the prior drug-paired context or cues without drug delivery. In both the self-administration and CPP procedures, the extinguished behaviors can be reinstated by the drugs used in the training sessions or the drug-paired cues or context (Mueller & Stewart, 2000; Parker & McDonald, 2000), which has been termed as reinstatement (Stretch, Gerber, & Wood, 1971). 2. Role of amygdala in drug memories assessed by drug-induced conditioned place preference 2.1. Cocaine and methamphetamine Learned associations between the environmental context or discrete cues and the reinforcing effects of cocaine have been consid-

ered to play significant roles in cocaine use and relapse (O’Brien et al., 1998). Our recent study revealed that the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in the BLA is a key molecule in the consolidation and reconsolidation of associative memories between cocaine-paired environmental cues and the reinforcing effects of cocaine in the CPP procedure (Li et al., 2010). In this study, we investigated whether the consolidation and reconsolidation of cocaine cue memories can be inhibited by microinjection of the Cdk5 antagonist b-butyrolactone into the BLA or CeA. We found that microinjection of b-butyrolactone into the BLA but not CeA immediately after cocaine training sessions disrupts the consolidation of cocaine cue memories, but this effect disappear when the antagonist was microinjected 6 h after the training sessions. The results indicate that Cdk5 activity in the BLA mediates the consolidation process of cocaine cue memories. Additionally, Cdk5 activity in the BLA is required for the reconsolidation of cocaine cue memories. These findings suggest that the BLA is a key brain area for various phases of cocaine cue memories. In addition to Cdk5, we recently demonstrated that the reconsolidation of cue memories associated with cocaine requires GSK-3b activation in the BLA (Wu et al., 2011). Several studies have indicated that different molecular mechanisms in the BLA complex are required for cocaine cue memories. Previous studies have demonstrated that phospholipase D-linked metabotropic glutamate receptor (mGluR) signaling, the protein kinase C (PKC) signaling pathway, and protein synthesis in the BLA are important for the expression of cue-conditioned responses to cocaine (Krishnan et al., 2011; Lai et al., 2008). The role of the BLA and signaling molecules in the retrieval of cocaine cue memories has been well established in the cocaine-induced CPP model (Lai et al., 2008). The expression of established cocaine-induced CPP can be blocked by systemic administration of anisomycin, a nonspecific protein synthesis inhibitor, 30 min before the retrieval test. A similar phenomenon can be mimicked by microinjection of anisomycin or cycloheximide into the BLA before the retrieval test, suggesting that the BLA is a critical region in the mediation of the retrieval of cocaine cue memories. To investigate the signaling pathways in the BLA, intra-amygdala infusion of the PKC inhibitor NPC 1543 or mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 blocked the expression of cocaine-induced CPP in a subsequent test without co-occurring locomotor activity holdback or aversive effects induced by the manipulations. The evidence provided by this experiment indicates that the PKC signaling pathway and downstream protein synthesis in the BLA control the retrieval of cocaine cue memories (Lai et al., 2008). The noradrenergic system is known to be required for the reconsolidation process after a stable memory has been activated, which has been well studied in both aversive and appetitive experience learning (Abrari, Rashidy-Pour, Semnanian, & Fathollahi, 2008; Bernardi, Lattal, & Berger, 2006; Debiec & Ledoux, 2004; Diergaarde, Schoffelmeer, & De Vries, 2006; Fricks-Gleason & Marshall, 2008; Przybyslawski, Roullet, & Sara, 1999; Robinson & Franklin, 2007). The involvement of the noradrenergic system in cocaine-related memory has been demonstrated in cocaine-induced CPP in animals (Bernardi et al., 2009). The impairment of reconsolidation of cocaine-induced CPP produced by post-retrieval systemic administration of propranolol suggests that b-adrenergic receptors are critical for the reconsolidation of cocaine memory. To determine the precise mechanism that mediates the impairment of reconsolidation of cocaine-induced CPP produced by post-retrieval systemic administration of propranolol, the nonspecific b-adrenergic receptor antagonist was replaced by specific b1, b2, and a1 receptor antagonists, and systemic administration was replaced with intra-BLA infusion. In addition to systemic administration, post-retrieval intra-BLA infusion of b2 and a1 receptor antagonists

Please cite this article in press as: Luo, Y.-X., et al. Role of amygdala in drug memory. Neurobiology of Learning and Memory (2013), http://dx.doi.org/ 10.1016/j.nlm.2013.06.017

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abolished the acquired cocaine-induced CPP, but this effect was absent if the retrieval process was omitted. Moreover, the b2 receptor antagonist ICI118,551 decreased the Fos response in the BLA induced by the CPP test. These findings demonstrate that b2 and a1 receptor mechanisms and specific noradrenergic signaling mechanisms in the BLA play a pivotal role in the reconsolidation of the initial cocaine memory (Bernardi et al., 2006). Notably, Théberge et al. found that both intra-NAc core and intra-BLA zif268 antisense oligodeoxynucleotide (ASO) infusions during memory reactivation impair the reconsolidation of cocaine cue memories (Theberge, Milton, Belin, Lee, & Everitt, 2010). However, zif268 ASO administration into the NAc core after memory reactivation does not affect the reconsolidation of the memory representations that underlie the conditioned reinforcing properties of a cocaine-paired conditioned stimulus, which is in contrast to the marked impairment observed previously following intra-BLA zif268 ASO infusions (Lee, Di Ciano, Thomas, & Everitt, 2005; Theberge et al., 2010). These results suggest that drug-memory reconsolidation in Pavlovian and instrumental conditioning settings involves distinct neuroanatomical mechanisms. The N-methyl-Daspartate (NMDA) glutamatergic receptor is involved in the process of extinction of conditioned associations, which has been demonstrated by a series of fear conditioning studies (Davis & Myers, 2002). Botreau et al. reported that both systemic and intra-BLA injections of D-cycloserine (an NMDA partial agonist) immediately after extinction training accelerate the pace of extinction of the original associations between the reinforcing effects of cocaine and the cocaine-paired environment, but these effects are abolished by a 4 h delayed delivery of D-cycloserine (Botreau, Paolone, & Stewart, 2006). Moreover, this effect is long-lasting and resistant to reinstatement, but when extinction procedures are intensive, D-cycloserine appears to have no additional benefit (Paolone, Botreau, & Stewart, 2009). The accelerated extinction of cocaine-induced CPP may be a consequence of the enhanced new associations that are mediated by NMDA receptors in the BLA. Additionally, a recent study examined the ability of phosphodiesterase (PDE) inhibitors to facilitate the extinction of drug memory. The blockade of PDE9 dose-dependently increases cyclic guanosine monophosphate (cGMP) in the hippocampus and amygdala, significantly facilitates extinction, and diminishes the reinstatement of cocaine-induced CPP, whereas the blockade of PDE4 or PDE10A has no significant effect on the extinction of cocaine-induced CPP (Liddie, Anderson, Paz, & Itzhak, 2012). As recapitulated above, various molecules and pathways in the amygdala are involved in different phases of cocaine cue memory in the cocaine-induced CPP model, suggesting that the amygdala plays a critical role in cocaine cue memory. To investigate the role of the BLA in the incentive motivation for cocaine that is usually induced by cocaine-associated cues, a BLA complex (BLC) lesion study was conducted and found that the BLA is necessary for the formation of cocaine-induced CPP and consolidation of extinction of established cocaine-induced CPP (Fuchs & See, 2002). Pretraining bilateral infusion of the excitotoxin NMDA into the BLC disrupts the acquisition of cocaine-induced CPP, whereas posttraining infusion impairs the subsequent extinction of cocaine-induced CPP. These results can be explained by the function of the BLC in the assessment of the incentive value of a cocainepaired environment. However, pretraining BLC lesions may abolish the rewarding effects of cocaine but do not disrupt the process of learning the association between cocaine reinforcement and the salient environment. Pretraining lesion of the amygdala using a site-specific infusion of quinolinic acid does not affect basal or cocaine-induced conditioned locomotion, whereas cocaine-induced CPP is completely blocked. These results indicate that the amygdala plays differential roles in cocaine-induced stimulus-reward conditioning (Brown & Fibiger, 1993). Additionally, lesion studies

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found that an intra-BLA infusion of lidocaine immediately after the retrieval of cocaine-induced CPP diminishes subsequent CPP performance, and Fos-staining results showed that BLA neurons are activated by the retrieval of cocaine-induced CPP, indicating that the BLA may be involved in the reconsolidation of cocaine cue memory (Tzeng et al., 2012). Amphetamine-associated environmental learning has been reported to increase the activity of excitatory synapses in the BLA in rats that underwent amphetamine-induced CPP training (Rademacher, Rosenkranz, Morshedi, Sullivan, & Meredith, 2010). Amphetamine-induced CPP training increases the activity of excitatory synapses in the BLA, assessed by in vivo intracellular recordings, suggesting that drug-associated environmental learning can change the structural and functional plasticity of the BLA. The role of the BLA in amphetamine-associated environmental learning has been well-studied using the CPP model. The amphetamine-induced CPP consolidation process is mediated by the amygdala (Hsu, Schroeder, & Packard, 2002). To verify this, posttraining intraamygdala infusion of bupivacaine blocks the formation of amphetamine-induced CPP, but an intra-amygdala infusion of bupivacaine 1 h after training does not block the formation of amphetamine-induced CPP, indicating that a time-dependent process in the amygdala underlies the consolidation of amphetamine-induced CPP (Hsu et al., 2002). The hippocampus and BLA are involved in the acquisition and expression of amphetamine-induced CPP (Hiroi & White, 1991). Pretraining electrolytic or excitotoxic lesions of the lateral nucleus of the amygdala but not CeA or BLA attenuates the formation of amphetamine-induced CPP. Additionally, electrolytic or excitotoxic lesions of the lateral nucleus of the amygdala after the training sessions blocks the expression of amphetamine-induced CPP in the subsequent test. The lateral nucleus of the amygdala but not CeA or BLA has been identified as a specific site involved in the acquisition and expression of amphetamine-induced CPP. Cholinergic muscarinic receptor function within the BLA also plays a critical role in the consolidation of amphetamine-induced CPP (Schroeder & Packard, 2002). Intra-BLA infusions of scopolamine immediately after training impaired the consolidation of amphetamine reward memory assessed in the CPP model. The amygdala has also been shown to regulate the extinction of amphetamine-related cue memories. Systemic or intra-amygdala infusion of glucose facilitated the extinction of amphetamine-induced CPP. Systemic glucose injection or intraBLA infusion of glucose immediately after the extinction session enhanced the extinction of amphetamine-induced CPP. The role of cholinergic muscarinic receptors within the BLA in the extinction of amphetamine reward memory appears to be time-dependent. Systemic or intra-amygdala delivery of a cholinergic muscarinic receptor agonist immediately after extinction training facilitates the formation of extinction memory (Schroeder & Packard, 2004). However, neither systemic nor intra-amygdala delivery of the cholinergic muscarinic receptor agonist or glucose 2 h after the extinction training session enhances the extinction of amphetamine-induced CPP. 2.2. Morphine Similar to cocaine, in morphine-associated memory, repeated associations between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling also form rewarding and aversive memories. Exposure to a morphinepaired environment increased Fos expression in many brain sites in rats that expressed morphine-induced CPP, including the dorsomedial striatum, central medial nucleus of the thalamus and BLA that participate in emotional learning processes. This hypothesis has been supported by brain lesion studies (Guo, Garcia, & Harlan, 2008). The CeA has been shown to be implicated in relapse to

Please cite this article in press as: Luo, Y.-X., et al. Role of amygdala in drug memory. Neurobiology of Learning and Memory (2013), http://dx.doi.org/ 10.1016/j.nlm.2013.06.017

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drug-seeking behavior induced by footshock stress (Wang, Luo, Ge, Fu, & Han, 2002). Another amygdala lesion study found that the amygdala plays an important role in the acquisition and expression of conditioned individual preference (CIP). Both pre- and post-CIP training lesions of the amygdala in mice revealed no preference for the stimulus in the test session (Borlongan & Watanabe, 1994). These results suggest that the amygdala is a specific area that mediates the acquisition and expression of conditioned discrimination behavior in mice. Using CPP and conditioned place aversion (CPA) paradigms, we recently investigated the molecular bases of the maintenance and persistence of morphine-related memories. Protein kinase M f (PKMf) is a key molecule in the maintenance of late long-term potentiation (LTP) and memory storage. We found that PKMf in the BLA is critical for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory and that PKMf in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues (He et al., 2011). In addition to the amygdala, PKMf in the NAc core is required for morphine cue memory storage. Morphine-induced CPP training is associated with increased PKMf protein levels in the NAc, and NAc core but not shell infusion of ZIP (the PKMf inhibitor-f inhibitory peptide) blocks the expression of morphine-induced CPP (Li et al., 2011). Functional interconnections between the medial PFC (mPFC), ventral tegmental area (VTA) and BLA have been reported to play an important role in the processing of associative memories linked to opiate-related cues (Koya et al., 2006; Langleben et al., 2008). A recent study found that NMDA receptor blockade in the prelimbic (PLC) region of the mPFC strongly potentiates the rewarding associative properties of both systemic and intra-VTA opiate administration via dopamine D1 and D2 receptor-dependent mechanisms (Bishop, Lauzon, Bechard, Gholizadeh, & Laviolette, 2011). Additionally, the potentiation of morphine reward is abolished by pharmacological inactive of the BLA, suggesting a functional interaction between inputs from presynaptic BLA glutamate release and dopamine receptor transmission within the PLC during the encoding and modulation of associative opiate reward learning. A recent study showed that inputs from the BLA to PLC modulate the processing of opiate-related extinction memory (Sun & Laviolette, 2012). Several studies have examined neurotransmitter systems in the processing of morphine-associated memories. For example, NMDA receptors in the CeA are involved in the acquisition and expression of morphine-induced CPP. Intra-CeA infusion of the noncompetitive NMDA receptor antagonist MK-801 dose-dependently inhibits morphine-induced CPP. However, prior to the test, intra-CeA infusion of NMDA itself but not MK-801 augments the expression of morphine-induced CPP (Rezayof, Golhasani-Keshtan, Haeri-Rohani, & Zarrindast, 2007). Moreover, the expression of morphine-induced CPP is inhibited by an intra-CeA infusion of a noncompetitive NMDA receptor antagonist, and the enhanced expression of morphine-induced CPP is induced by an intra-CeA infusion of NMDA. The cholinergic system in the BLA has been reported to play a critical role in morphine-induced CPP. Zarrindast et al. reported that an intra-BLA infusion of the antimuscarinic receptor drug atropine or nicotine receptor antagonist mecamylamine dose-dependently inhibits the formation of morphine-induced CPP, indicating that muscarinic and nicotine receptor mechanisms in the BLA mediate the acquisition of morphine-induced CPP. The role of c-aminobutyric acid A (GABAA) receptors in the BLA in the regulation of morphine-induced CPP has been reported (Zarrindast, Fattahi, Rostami, & Rezayof, 2005). An Intra-BLA infusion of bicuculline, a GABAA receptor antagonist but not a GABAA receptor agonist prior to the test significantly attenuates the expression of morphine-induced CPP. These results indicate

that GABAA receptors in the BLA at least partially mediate morphine-induced CPP (Zarrindast et al., 2004). The mesolimbic dopamine system contributes to the mediation of the rewarding effects of abused drugs, in which dopaminergic fibers project from the VTA to NAc (Koob, 1992). The CeA contains many dopamine terminals because of its connection to the NAc and receives dopaminergic afferents from the VTA (Kilts & Anderson, 1987; Woodward, Chang, Janak, Azarov, & Anstrom, 1999). Studies of the dopamine receptors involved in drug-induced CPP indicated that the amygdala plays a role in the rewarding effects of abused drugs (Lu, Zeng, Liu, & Ceng, 2000; O’Dell, Sussman, Meyer, & Neisewander, 1999). Rezayof and Zarrindast reported that D2 and D1 receptors in the CeA play a crucial role in the acquisition and expression of morphine-induced CPP in rats. Intra-CeA infusion of the D1 receptor agonist SKF38393 or D2 receptor agonist quinpirole enhances the acquisition of morphine-induced CPP, whereas intra-CeA infusion of the D1 receptor antagonist SCH23390 or D2 receptor antagonist sulpiride attenuates the acquisition of morphine-induced CPP. Additionally, infusions of both a D1 receptor agonist and antagonist into the CeA attenuate the expression of morphine-induced CPP, but only intra-CeA infusion of the D2 receptor agonist abolishes the expression of morphine-induced CPP. These results indicate that both D1 and D2 receptors in the CeA contribute to the acquisition and expression of morphine-induced CPP (Rezayof et al., 2002; Zarrindast, Rezayof, Sahraei, Haeri-Rohani, & Rassouli, 2003). Recently, some studies identified a novel switching mechanism between dopamine D1 and D2 receptor transmission in the BLA-NAc shell pathway, which controls opiate reward signaling and depends on the state of opiate exposure. Using D1 and D2 receptor antagonists and agonists, researchers found that D1 receptor transmission in an opiate-naive state controls the acquisition of associative opiate reward memory. In an opiate-dependent and -withdrawn state, D2 receptor transmission controlled opiate reward encoding. This opiate state-dependent role of BLA D1/D2 transmission was confirmed by single-unit in vivo extracellular recordings performed in NAc neurons. Additionally, this switch is regulated by downstream protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) signaling in the BLA (Lintas et al., 2011) and mediated by NMDA transmission in the NAc shell (Lintas et al., 2012). These findings provide further evidence of the importance of amygdala-striatal connections during the processing of opiate-related reward memories. Molecular mechanisms of appetitive and aversive memories associated with morphine has been widely studied. Calcium/calmodulin-dependent protein kinase II (CaMKII), an important molecule for memory, has been reported to be involved in morphine-induced CPP (Lu et al., 2000). Intra-amygdala infusion of the CaMKII inhibitor KN-62 attenuates the maintenance of morphine-induced CPP without affecting morphine physical dependence and withdrawal symptoms, suggesting that the amygdala is involved in rewarding memory processes rather than the rewarding effects of drugs of abuse. Neurokinin-1 (NK-1), the preferred receptor for the neuropeptide substance P (SP) in the amygdala, plays an important regulatory role in morphine reward. The ablation of neurons that express NK-1 receptors in the amygdala using the neurotoxin substance P-saporin reduce the rewarding effects of morphine in the CPP model, indicating that the amygdala is an important area for the regulatory function of NK-1 receptors in morphine reward (Gadd, Murtra, De Felipe, & Hunt, 2003). Neuropeptide S, a 20-amino-acid bioactive peptide, was found in some brain areas that are related to the modulation of the rewarding properties of abused drugs, including the amygdala, VTA, and substantia nigra (Xu et al., 2004). Administration of NPS combined with morphine on conditioning days abolishes the acquisition of morphine-induced CPP, and NPS administration 15 min prior to

Please cite this article in press as: Luo, Y.-X., et al. Role of amygdala in drug memory. Neurobiology of Learning and Memory (2013), http://dx.doi.org/ 10.1016/j.nlm.2013.06.017

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the test blocks the expression of morphine-induced CPP in mice. Furthermore, NPS itself does not induce CPP or CPA or affect locomotor activity on the test day. These results reveals that NPS can affect the rewarding effects of opiates (Li et al., 2009). Several studies have investigated the mechanisms of the reconsolidation of morphine-associated memories. A recent study showed that appetitive and aversive addiction memories share common neural substrates in the BLA, such as protein synthesis and b-adrenergic receptor activation, but the specific neurotransmitter mechanism of the reconsolidation of appetitive and aversive memories associated with morphine can be disassociated (Wu, Li, Yang, & Sui, 2012). The interaction between the stress system in the amygdala and addiction has been reviewed (Koob, 2009). Glucocorticoid receptors in the BLA are involved in the mechanisms of the impairment of morphine cue memory by post-retrieval stress. Stress immediately after reexposure to a previous morphinepaired environment impairs the reconsolidation of morphine-induced CPP, and an intra-BLA but not intra-CeA or systemic injection of the glucocorticoid receptor (GR) antagonist RU38486 abolishes this impairment. This evidence supports the conclusion that GRs in the BLA mediate the process that disrupts the reconsolidation of morphine cue memory by post-retrieval stress exposure (Wang, Zhao, Ghitza, Li, & Lu, 2008). The response to drug-paired cues in rats has been shown to be progressively augmented by time after drug withdrawal in cocaine, heroin and methamphetamine self-administration studies (Grimm, Hope, Wise, & Shaham, 2001; Neisewander et al., 2000; Shalev, Morales, Hope, Yap, & Shaham, 2001; Shepard, Bossert, Liu, & Shaham, 2004), which has been termed as the ‘‘incubation of drug craving.’’ Extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in the CeA play a pivotal role in mediating the incubation of opiate craving in the rat CPP model. Progressive increases in CPP scores over the first 14 days after four training sessions were found in rats that received lowdose (1 or 3 mg/kg, i.p.) but not high-dose (10 mg/kg, i.p.) morphine. The progressive increase in CPP scores was accompanied with increased ERK activity, measured by ERK phosphorylation, and CREB, which is a downstream target of ERK in the CeA but not BLA (Li et al., 2008). The study showed that the ERK pathway in the CeA is involved in the incubation of morphine craving in the rat CPP model. Although opiate addiction is linked to the intrinsic reinforcing effects of the drug, the development of compulsive drug seeking may be motivated by physical dependence and avoidance of the aversive effects of withdrawal. To better characterize the motivational component of opiate withdrawal and memory traces in the brain, the CPA paradigm was used to study the neural pathways recruited in aversive drug memories. Reexposure to a withdrawal-paired environment was found to specifically induce conditioned c-fos responses in the extended amygdala (i.e., a superstructure that includes the CeA, bed nucleus of the stria terminalis [BNST], and NAc), VTA, hippocampus, BLA, locus coeruleus (LC), and hypothalamus (Frenois, Stinus, Di Blasi, Cador, & Le Moine, 2005). A recent study found that Arc/Arg3.1 is a crucial mediator of actin polymerization in the regulation of synaptic plasticity and expression of CPA, and their synaptic interaction in the amygdala promoted GluR1- and GluR2-containing a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) endocytosis in a GluR2-dependent manner (Liu et al., 2012). Additionally, aversive memories of opiate withdrawal, like other types of memory, undergo anatomical reorganization following long-term abstinence, with a shift from extended amygdala regions to cortical areas (Lucas, Frenois, Cador, & Le Moine, 2012). Therefore, the amygdala is hypothesized to be a key brain region where negative reinforcement mechanisms drive drug-seeking behaviors.

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2.3. Ethanol Similar to cocaine, amphetamine, and morphine, ethanol-induced CPP after long-term abstinence or extinction can be elicited by ethanol-paired environmental cues that are associated with reinforcing effects in prior Pavlovian conditioning (Ciccocioppo, Angeletti, & Weiss, 2001; Ciccocioppo, Lin, Martin-Fardon, & Weiss, 2003; Ciccocioppo, Martin-Fardon, & Weiss, 2002; Dayas, Liu, Simms, & Weiss, 2007; Krank & Wall, 1990; Nie & Janak, 2003; Zironi, Burattini, Aicardi, & Janak, 2006). Behavioral studies have indicated the importance of the CeA in the compulsive consumption of alcohol (Koob, 2004) and neurobiological mechanisms in the CeA that underlie compulsive alcohol consumption. They reported that non-NMDA synaptic transmission in CeA neurons significantly increases and that intra-CeA infusion of CNQX, a non-NMDA receptor antagonist, blocks ethanol-induced CPP (Zhu, Bie, & Pan, 2007). These results suggest that non-NMDA glutamate receptors in the CeA are required for ethanol-induced reward memory. A recent study found that chronic intermittent ethanol (CIE) exposure and withdrawal increase AMPAR surface expression and subunit phosphorylation and change the protein levels or phosphorylation status of CaMKII and PKC, which eventually contribute to the induction and expression of postsynaptic LTP in the amygdala (Christian, Alexander, Diaz, Robinson, & McCool, 2012). A site-specific electrolytic lesion study revealed that the acquisition of ethanol-induced CPP depends on the NAc and amygdala, whereas the expression of ethanol-induced CPP depends on an amygdala-dependent mechanism. However, the specific neurotransmitters in each area that contribute to the acquisition, expression, and extinction of ethanol-induced conditioned reward have not been delineated (Gremel & Cunningham, 2008). To identify the specific mechanisms within these nuclei, pretest infusions of the D1/D2/D3 receptor antagonist flupenthixol and NMDA receptor antagonist AP-5 were used. Gremel and Cunningham demonstrated that BLA dopamine receptors and NAc NMDA receptors are critical for the expression of the ethanol-induced conditioned effect (Gremel & Cunningham, 2009). l-Opioid receptors (MORs) are required for the rewarding effects and associated behavior induced by opioids and alcohol (Contet, Kieffer, & Befort, 2004). Notably, Bie et al. demonstrated that repeated alcohol exposure recruited new functional d-opioid receptors (DORs) in CeA glutamate and GABA synapses and that ethanol-recruited DORs located on presynaptic glutamatergic terminals and their activation inhibited presynaptic glutamate release and synaptic activity, which may be involved in the expression or maintenance of ethanol-induced CPP (Bie, Zhu, & Pan, 2009). In addition to opioid receptors, nicotinic acetylcholine receptors may also be involved in the conditioned effects induced by ethanol. Interestingly, Zarrindast et al. found that administration of nicotine plus ethanol into the CA1 area of the hippocampus or BLA during the conditioning phase significantly induced strong CPP, and this effect was reversed by the nicotinic acetylcholine receptor antagonist mecamylamine. However, only a pretest injection of nicotine in the BLA and not CA1 potentiated the expression of ethanol-induced CPP. Therefore, the nicotinic cholinergic system in the BLA may be involved in the acquisition and expression of ethanol-induced CPP, whereas the CA1 area is only involved in acquisition (Zarrindast, Meshkani, Rezayof, Beigzadeh, & Rostami, 2010). Ethanol can also functionally interact with the endocannabinoid system to mediate reward or aversion. Low doses of ethanol cannot induce CPP or CPA, and injections of arachidonylcyclopropylamide (ACPA), a cannabinoid CB1 receptor agonist, into the VTA, BLA, or ventral hippocampus (VH) combined with ethanol during the conditioning or testing phase induce CPP or CPA (Rezayof, Ghandipour, & Nazari-Serenjeh, 2012). These results suggest a complex correlation

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between cannabinoid CB1 receptors and ethanol in the acquisition and expression of CPP that strongly depends on the brain site of the injection and dose of the agonist applied. In conclusion, the amygdala plays a critical role in each phase of drug-related memory assessed by CPP induced by abused drugs, including cocaine, heroin, and ethanol. The CPP model tests a well-trained animal in a drug-free state for its preference for an environment previously paired with drug delivery, and the results of such studies are rarely obscured by unconditioned stimuli, including drug reinforcement. However, human subjects administer more abused drugs compared with the doses typically used in an animal CPP model. Thus, the evidence provided by the CPP model has limitations that reflect the nature of compulsive drug seeking and drug taking (see Table 1). 3. Role of amygdala in drug memories assessed by drug selfadministration The self-administration model closely mimics the relapse to drug intake observed in human addicts. The role of the amygdala in self-administration will be discussed in this section. 3.1. Cocaine The expression of zif268 and the activity-regulated cytoskeleton-associated gene (arc), which are regulated by cocaine-associated stimuli and have been implicated in mediating the cellular events of drug-associated learning processes (Hearing, See, & McGinty, 2008; Lee et al., 2005; Robbins et al., 2008; Zavala, Browning, Dickey, Biswas, & Neisewander, 2008), increases in the BLA after reexposure to a context previously paired with cocaine intake after 22 h or 15 days of abstinence from cocaine self-administration in rats that received 10 days of cocaine self-administration (Hearing et al., 2008). The induction of arc and zif268 expression in the BLA when rats are reexposed to the previous drug-paired environment indicates that the BLA participates in encoding the associative drug memory. Inactivation of different parts of the amygdala have demonstrated a critical role for the amygdala in the modulation of cocaine-seeking behavior (Mashhoon, Wells, & Kantak, 2010). The incentive motivational effects of cocaine-related cues have been assessed by determining c-fos mRNA and Fos protein expression in several brain locations. In cocaine-extinguished animals, cues induced c-fos mRNA and Fos protein expression in the PFC, VTA, dorsal striatum, and NAc. Cocaine-seeking behavior induced Fos protein expression in the agranular insula (AgI) and BLA, suggesting that neural activity in the AgI and BLA participates in the process of cocaine cue-elicited incentive motivation for cocaine seeking (Kufahl et al., 2009). The blockade of drug memory reconsolidation can dampen the longlasting vulnerability to drug cue-elicited relapse to drug-seeking and drug-taking behavior in operant cocaine self-administration models. In this procedure, shortly before reexposure to cocaineassociated stimuli, infusion of zif268 ASO into the BLA abolishes the cue-induced reinstatement of cocaine seeking and subsequently impairs cue-maintained cocaine seeking in a second-order schedule of reinforcement (Lee, Milton, & Everitt, 2006). This finding indicates that the BLA is important for conditioned reinforcement and incentive processes, and zif268 is specifically unregulated in the BLA by reexposure to cocaine-associated stimuli. Therefore, local infusion of zif268 ASO into the BLA prior to reexposure to cocaine-associated stimuli impaired the reconsolidation of both young and old drug memories assessed by a secondorder schedule of reinforcement and cue-induced reinstatement, suggesting a potential therapeutic intervention to prevent relapse in human addicts. Several studies have investigated the molecular

mechanisms of memory reconsolidation in the amygdala. Using the self-administration paradigm, bilateral intra-BLA infusions of the PKA inhibitor Rp-cAMPS given immediately following light/ tone stimulus reactivation decrease subsequent cue-induced reinstatement and responding with a conditioned reinforcer but had no effect on cocaine-induced reinstatement, indicating that memory reconsolidation for a cocaine-paired stimulus critically depends on PKA activity in the amygdala (Sanchez, Quinn, Torregrossa, & Taylor, 2010). Another recent study showed that ERK activation in the BLA but not NAc core is required for the reconsolidation of context-response cocaine-associative memories (Wells et al., 2012), which is not consistent with previous results that showed that ERK activation in the NAc core mediated the reconsolidation of Pavlovian cocaine memories (Miller & Marshall, 2005b). These results should be interpreted with caution considering that distinct neuroanatomical mechanisms may underlie contextual drug-memory reconsolidation in Pavlovian and instrumental settings. Several studies have also investigated the functional interactions between different brain regions during different phases of memory. Rats were trained to self-administer cocaine in a distinct environment (i.e., cocaine-paired context), followed by extinction training (i.e., extinction context). On the test day, the rats received unilateral microinfusions of baclofen + muscimol or vehicle into the BLA and either the contralateral or ipsilateral dorsomedial PFC (dmPFC) or dorsal hypothalamus (DH). The results showed that an intrahemispheric interaction between the BLA and DH/ dmPFC is required for the expression of drug context-induced cocaine-seeking behavior (Fuchs, Eaddy, Su, & Bell, 2007). Another study reported that asymmetric inactivation of the rostral BLA (rBLA) and PLC significantly attenuates the reinstatement of cocaine-seeking behavior compared with vehicle treatment using a second-order procedure, in which unilateral inactivation of the rBLA or PLC in rats does not disrupt the reinstatement induced by cocaine cues. These findings suggest that an intrahemispheric interaction between the rBLA and PLC plays a pivotal role in regulating the reinstatement of cocaine-seeking behavior induced by reexposure to cocaine cues (Mashhoon et al., 2010). Similarly, Wells et al. found that intrahemispheric BLA/DH interactions are involved in the reconsolidation of cocaine-related associative memories, thereby facilitating drug context-induced cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior (Wells et al., 2011). Additionally, Szalay et al. recently found that the rBLA and dorsal subiculum need to be functionally activated simultaneously in at least one brain hemisphere for the acquisition of cocaine cue extinction learning (Szalay, Morin, & Kantak, 2011). However, the mechanism by which different brain regions interact to regulate cocaine associative memories is unclear (Aantaa, Kanto, Scheinin, Kallio, & Scheinin, 1990). The role of the BLA in mediating the consolidation of both the association of cocaine-related stimuli and extinction of the established cocaine memory via Na+ channel-mediated mechanisms has been reported. Intra-BLA infusion of the Na+ channel blocker tetrodotoxin (TTX) immediately after classical conditioning or reinstatement testing differentially affects subsequent cocaineseeking behavior. Tetrodotoxin infusion at the former time point attenuates cocaine cue-induced reinstatement, whereas TTX infusion at the later time point impairs the consolidation of the extinction of established associations between cocaine and cocaine cues on the day after the reinstatement test (Fuchs, Feltenstein, & See, 2006). Distinct subregions of the amygdala have been shown to play unique roles in the acquisition and expression of cocaine-seeking behavior assessed by lever-pressing induced by drug-paired cues in animal models of relapse. Reversible inactivation of the BLA or CeA produces different effects on the acquisition and expression

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Y.-X. Luo et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx Table 1 Role of amygdala in drug memories assessed by conditioned place preference. Brain region

Main findings

Strain/sex

Reference

BLA

Li et al. (2010)

BLA

Cdk5 mediates consolidation and reconsolidation of memories of cocaine-associated environmental cues PKC signaling pathway in the BLA mediates retrieval of cocaine cue memories

BLA

a1- and b2-specific adrenergic antagonists administered immediately after retrieval disrupted

BLA

cocaine-induced CPP Post-retrieval propranolol disrupts cocaine-induced CPP

BLA

D-Cycloserine

BLA

Excitotoxic lesions of the BLA disrupt cocaine-seeking behavior and CPP

Amygdala and hippocampus BLA

Increased cGMP plays a role in the consolidation of extinction learning

Amygdala

Rats that exhibited amphetamine-induced CPP exhibit an increase in the activity of excitatory synapses The amygdala mediates the consolidation of amphetamine-induced CPP

BLA

Post-training BLA damage disrupts the expression of amphetamine-induced CPP

BLA

Immediate posttraining scopolamine blocks the acquisition of food- and amphetamine-induced CPP

Amygdala

Post-extinction oxotremorine facilitates the extinction of amphetamine-induced CPP

BLA CeA BLA

Inactivation of neural activity in the BLA immediately following retrieval impairs the subsequent expression of cocaine-induced CPP Intra-CeA infusion of NMDA increases the expression of morphine-induced CPP GABAA receptors in the BLA mediate morphine-induced CPP

Male Sprague– Dawley rats Male C57BL/6J mice Male Sprague– Dawley rats Male Sprague– Dawley rats Male Long-Evans rats Male Sprague– Dawley rats Male B6129S mice Male Sprague– Dawley rats Male Long–Evans rats Male Long–Evans rats Male Long–Evans rats Male Long–Evans rats Male C57BL/6NJ mice Male Wistar rats Male Wistar rats

CeA

D2 receptors mediate the acquisition and expression of morphine-induced CPP

Male Wistar rats

Amygdala and hippocampus Amygdala

CaMKII mediates morphine-induced CPP

BLA

Stress impairs the reconsolidation of drug memory via glucocorticoid receptors

CeA

ERK and CREB protein mediate the incubation of opiate craving

NAc, VTA, CeA, and BLA Amygdala

Specific brain areas mediate the process of relapse to drug seeking

Amygdala

Ethanol-induced CPP requires the involvement of dopamine receptors in the amygdala

Male Sprague– Dawley rats NK1 receptor knockout mice Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male DBA/2J mice Male DBA/2J mice

BLA BLA

A functional interaction exists between D1/D5 receptors and group I mGluRs via PLD in synaptic plasticity in the amygdala associated with cocaine-related cues GSK-3b activity in the BLA mediates the reconsolidation of cocaine-related cue memories

BLA and NAc

Identification of a dopamine receptor-mediated opiate reward memory switch in the BLA-NAc circuit

BLA

PKMf maintains drug reward and aversion memory in the BLA

BLA, VTA, plPFC

A functional interaction between inputs from the VTA and BLA within the PLC modulates associative opiate reward information PKMf is involved in retrieval-extinction procedure in drug memories

BLA Amygdala

accelerates extinction of cocaine-induced CPP

NK-1 plays an important regulatory role in morphine reward

Non-NMDA glutamate receptors mediate synaptic actions and reward behavior induced by ethanol

BLA and NAc

An increase in synaptic Arc/Arg3.1 expression in the amygdala is crucial for the expression of aversive memory associated with drug withdrawal The inhibition of protein synthesis disrupts the reconsolidation of morphine-induced CPP and CPA, and propranolol disrupts the reconsolidation of CPA but not CPP A functional link exists between BLA and plPFC specifically during the acquisition and extinction phases of opiate reward memory Dopamine D1/D2 receptor-mediated opiate reward memory switch within the BLA?NAc shell circuit

PFC, amygdala, and hippocampus

Affective memories linked to opiate withdrawal undergo anatomical reorganization, including extended amygdala regions and cortical areas

BLA BLA and plPFC

Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats

Lai et al. (2008) Bernardi et al. (2009) Bernardi et al. (2006) Botreau et al. (2006) Fuchs et al. (2002) Liddie et al. (2012) Rademacher et al. (2010) Hsu et al. (2002) Hiroi and White (1991) Schroeder and Packard (2002) Schroeder and Packard (2004) Tzeng et al. (2012) Rezayof et al., 2007 Zarrindast et al. (2004, 2005) Rezayof et al. (2002) Zarrindast et al. (2003) Lu et al. (2000) Gadd et al. (2003) Wang et al. (2008) Li et al. (2008) Wang et al. (2002) Zhu et al. (2007) Gremel and Cunningham (2008) Krishnan et al. (2011) Wu et al. (2011) Lintas et al. (2011) He et al. (2011) Bishop et al. (2011) Xue et al. (2012) Liu et al. (2012) Wu et al. (2012) Sun and Laviolette (2012) Lintas et al. (2012) Lucas et al. (2012)

BLA, basolateral amygdala; CeA, central nucleus of the amygdala; NAc, nucleus accumbens; VTA, ventral tegmental area; PFC, prefrontal cortex; plPFC, prelimbic prefrontal cortex; ACC, anterior cingulate cortex; Cdk5: cyclin-dependent kinase 5; CPP, conditioned place preference; NMDA, N-methyl-D-aspartate; GABAA, c-aminobutyric acid type A; D1, dopamine 1 receptor; D2, dopamine 2 receptor; CaMKII, calcium/calmodulin-dependent protein kinase II; NK-1, neurokinin-1; ERK, extracellular signal-regulated kinase; CREB, cyclic adenosine monophosphate response element binding protein; PLD, phospholipase D; GSK-3b, glycogen synthase kinase 3b; PKMf, protein kinase M f; Arc/arg3.1, activity-regulated cytoskeletal-associated protein; PKA, protein kinase A; NPY, neuropeptide Y; mGluR, metabotropic glutamate receptor.

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of the conditioned reinforcing effects of drug-paired stimuli (Kruzich & See, 2001). Lesions of the BLA using site-specific infusion of TTX disrupt both the acquisition and expression of the conditioned reinforcing effects produced by previously drug-paired stimuli, but lesions of the CeA disrupt only expression. Compared with permanent lesions, reversible inactivation can be used to examine the role of discrete brain structures in different stages of learning. Using a reversible inactivation method in an animal model of relapse, the roles of the dorsolateral caudate putamen (dICPu) and BLA in the consolidation of cocaine cue associative learning have been investigated (Gabriele & See, 2010). Infusion of a GABA receptor agonist into the BLA but not dICPu decreased cocaine seeking in rats reinstated by previously cocaine-paired cues. These results showed that the BLA but not dICPu is required for the consolidation of cocaine cue associative learning in a reinstatement model of cocaine seeking. The advantage of this model is that it allows for the assessment of both the acquisition and expression of stimulusdrug associations because it bypasses the invariable multiple conditioning trials required during chronic drug self-administration. Investigating the neural substrates of acquisition becomes convenient, because, similar to animal models of aversive conditioning, this model requires only one-trial acquisition. As reviewed above, specific structures of the amygdala play critical roles in the reinstatement of cocaine seeking induced by previous cocaine-paired cues. Using the conditioned-cued reinstatement model, substantial studies have demonstrated that many specific neurotransmitter inputs to the BLA underlie the process of reinstatement induced by conditioned cocaine-paired cues (Gabriele & See, 2010; Hearing et al., 2008; Kruzich & See, 2001; Lee et al., 2006; Mashhoon et al., 2010). Dopamine D1 receptors in the caudal and rostral BLA play disassociated roles in cocaineseeking behavior. To directly demonstrate the importance of D1 receptor mechanisms in the rostral and caudal BLA, the D1 receptor agonist SKF 81297 and D1 receptor antagonist SCH 23390 were infused into the rostral and caudal BLA, respectively. Intra-caudal but not intra-rostral BLA infusion of SKF 81297 increases cocaine-seeking behavior, but opposite effects are produced by Intra-caudal but not intra-rostral BLA infusion of SCH 23390 (Mashhoon, Tsikitas, & Kantak, 2009). However, in the reinstatement test, intra-rostral but not intra-caudal BLA infusion of SKF 81297 increases cocaine-seeking behavior, and SCH 23390 infusion attenuates cocaine-seeking behavior. These findings indicate that D1 receptors in the caudal and rostral BLA contribute to the control of cocaine-seeking behavior during different phases of the development of addiction. A second-order schedule model was used to assess reinstatement and showed that this phenomenon is dependent on dopamine D3 receptors in the BLA. In this procedure, intra-amygdala but not intra-NAc shell infusion of the D3 receptor antagonist SB-277011-A markedly attenuates responding for cocaine on the active lever under a second-order schedule of reinforcement (Di Ciano, 2008). D2/D3 receptors in the CeA have been shown to be involved in cocaine seeking (Thiel et al., 2010). Prior to examining cue- and cocaine-induced reinstatement of cocaine-seeking behavior, intra-CeA infusion of the D2 receptor agonist 7-OH-DPAT but not D1 receptor agonist SKF-38393 decreases reinstatement, suggesting that D3 receptors in the CeA are sufficient to modulate the incentive motivational effects of cocaine-related cues and cocaine priming. See et al. reported that dopamine, but not glutamate, receptors in the BLA underlie the conditioned reinstatement of cocaine-seeking behavior. Intra-BLA infusion of the D1 receptor antagonist SCH 23390 or a combination of SCH 23390 and the D2/D3 receptor antagonist raclopride significantly attenuate reinstatement induced by conditioned cocaine-associated cues without affecting cocaine self-administration. However, the administration of raclopride alone or an NMDA receptor or AMPA receptor antagonist has no effects on the reinstatement of

cocaine-seeking behavior induced by conditioned cues, demonstrating that a D1 receptor-dependent mechanism in the BLA underlies the reinstatement of cocaine-seeking behavior elicited by conditioned cocaine-associated cues (See, Kruzich, & Grimm, 2001). In addition to dopamine receptors, glutamate receptors are also involved in both cue- and cocaine-induced cocaine-seeking behavior (Zavala, Browning, Dickey, Biswas, & Neisewander, 2008). Administration of AMPA receptor antagonist NBQX immediately before test significantly dampens cocaine-associated cues induced reinstatement in cocaine self-administrated rats following extinction training or not. Fos protein expression was simultaneously decreased in a region-specific manner, including in the cingulate cortex, orbitofrontal cortex, BLA and NAc core, suggesting that glutamate systems are involved in the activation of subregions of the neuronal circuitry activated by cocaine-associated cues after abstinence from cocaine use. In second-order schedules of drug reinforcement, the response is maintained by contingent presentation of drug-paired stimuli, which served as conditioned reinforcement factors for novel instrumental behavior learning (Bergman, Madras, Johnson, & Spealman, 1989; Everitt & Robbins, 2000; Goldberg & Gardner, 1981). The disruption of the reconsolidation of drug-related memories can attenuate the cue-induced maintenance of and relapse to cocaine seeking, suggesting a potential strategy for treating drug addiction (Lee et al., 2005; Miller & Marshall, 2005a). Under a second-order schedule of reinforcement, the blockade of the reconsolidation of drug-related memories through intra-BLA infusion of zif268 ASO immediately prior to reexposure to a cocaine-associated stimulus markedly impairs both subsequent cue-maintained cocaine-seeking behavior and the cue-induced reinstatement of and relapse to cocaine seeking. Additionally, the glutamate system has been implicated in the regulation of drug-seeking behavior by mediating the reconsolidation of drug memories (Milton, Lee, Butler, Gardner, & Everitt, 2008). IntraBLA infusion or systemic delivery of an NMDA receptor antagonist before the drug memory reactivation session disrupts subsequent conditioned instrumental learning, in which cocaine-paired cues served as the reinforcer. This impairment produced by the NMDA receptor antagonist is reactivation-dependent. Furthermore, the impairment was reflected by disruption of the reconsolidation of both old drug-related memories and recent cocaine-maintained instrumental behavior, suggesting a potential intervention for relapse in drug addiction (Lee et al., 2005; Lee et al., 2006; Milton et al., 2008). The glutamate system in the CeA has been shown to be involved in the expression of the incubation of cocaine-seeking behavior, defined as a progressive time-dependent increase in drug-seeking behavior induced by previous cocaine-paired cues during the first months of withdrawal from cocaine self-administration (Grimm et al., 2001; Lu, Grimm, Dempsey, & Shaham, 2004; Lu, Uejima, Gray, Bossert, & Shaham, 2007). Both systemic and intra-CeA infusions of the mGluR2/3 agonist LY379268 significantly dampens the progressive increase in cocaine-seeking behavior, reflected by extinction responding in the incubation test on day 21, indicating a potential role of mGluR2/3 in the CeA in the prevention of drug relapse (Lu et al., 2007). The ERK signaling pathway in the CeA but not BLA plays a pivotal role in the incubation of cocaine-seeking behavior in a rat model of craving and relapse (Lu et al., 2004). Additionally, NMDA-dependent mechanisms in the BLA participate in the control of the acquisition and consolidation of drug memory that contribute to cocaine-seeking behavior (Feltenstein & See, 2007). In summary, the amygdala plays both structural and functional roles in processing cocaine-stimulus associations that may underlie cocaine addiction.

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3.2. Heroin The pivotal role of the amygdala in conditioned cocaine-associated cue-induced relapse to cocaine seeking was discussed above. Whether the amygdala plays similar roles in the modulation of other drug-stimulus associations will be discussed in the following sections. An inactivation study identified a role of the BLA in opiatepaired stimulus learning. Inactivation of the BLA induced by TTX abolishes the conditioned cue-induced reinstatement of heroinseeking behavior, similar to the effect seen in cocaine self-administration studies. These results indicate that neural activity in the BLA is a critical component of conditioned heroin-associated cueand heroin-induced reinstatement of heroin-seeking behavior (Fuchs & See, 2002). Another study of excitotoxic lesions of the BLA that used second-order schedules of heroin self-administration further confirmed the role of the BLA in the acquisition of heroin-seeking behavior in rats (Alderson, Robbins, & Everitt, 2000). Lesion of the BLA using site-specific infusion of quinolinic acid prior to heroin self-administration does not affect the acquisition of heroin self-administration under either a continuous reinforcement schedule or second-order schedule, which is in marked contrast to the effects of BLA lesions on the acquisition of cocaine-seeking behavior. Such opposing results suggest that the BLA is not an indispensable component of the acquisition of opiate-stimulus associations. Disruption of the reconsolidation of conditioned withdrawal memories in the BLA reduces the suppression of heroin-seeking behavior in rats, demonstrating a critical role for the BLA in the reconsolidation of aversive drug memories. IntraBLA infusion of zif268 ASO prior to activation of the conditioned stimulus-withdrawal memories abolishes the conditioned suppression of heroin-seeking behavior in a reactivation-dependent manner, supporting a common mechanism in the BLA in both appetitive and aversive drug memories that undergo a protein synthesis-dependent reconsolidation process (Hellemans et al., 2006). Early spontaneous withdrawal from heroin self-administration produces region- and time-dependent changes in the phosphorylation of GluR1, ERK and CREB, and the mRNA levels of the stress responsive neurohormone arginine vasopressin (AVP), such as increased GluR1S845 phosphorylation and AVP mRNA levels in the amygdala, which contributes to the effect of negative emotional states on drug-seeking behavior (Edwards, Graham, Whisler, & Self, 2009). Behaviorally, the selective V1b receptor antagonist SSR149415 dose-dependently attenuates footshock-induced reinstatement and blocks heroin-induced reinstatement, suggesting that AVP-V1b systems may be a critical component of the neural circuitry that underlies the aversive emotional consequences of drug withdrawal and the effect of negative emotional states on drug-seeking behavior (Zhou, Leri, Cummins, Hoeschele, & Kreek, 2008). The CB1 receptor antagonist SR141716A also dose-dependently reduces the cue-induced reinstatement of heroin seeking, but the target brain regions are the NAc core and mPFC but not the BLA (Alvarez-Jaimes, Polis, & Parsons, 2008). We recently reported a memory retrieval-extinction procedure that can prevent drug craving and relapse in rat models of relapse and abstinent heroin addicts. Extinction experience within the reconsolidation time window after retrieval (i.e., daily retrieval of drug-associated memories 10 min or 1 h but not 6 h before extinction sessions) decreased drug- and cue-induced drug preference and relapse in rats and cue-induced drug craving in humans. The memory retrievalextinction manipulation with a 10-min but not 6-h delay potentiates extinction-induced increases in PKMf expression in the infralimbic cortex and extinction-induced decreases in PKMf expression in the BLA. These results indicate that molecular mechanisms in the BLA underlie the memory retrieval-extinction procedure and that the behavioral procedure is a promising

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nonpharmacological method for treating addition. However, the specific mechanisms are still unknown (Xue et al., 2012). Similar to cocaine-stimulus associations, the important role of the BLA in learning opiate-stimulus associations has been reviewed above. However, the BLA also plays distinct roles in learning cocaine- and opiate-stimulus associations, such as different effects of amygdala lesions on the acquisition of heroin and cocaine selfadministration (Alderson et al., 2000). 3.3. Ethanol and nicotine Alcohol self-administration studies have shown that alcoholassociated cues elicit drug-seeking behavior in animals trained to self-administer alcohol, even after protracted abstinence (Bienkowski et al., 2004; Shalev, Grimm, & Shaham, 2002). As reviewed above, the amygdala complex is involved in cocaine- and opiate-related memories in the self-administration procedure. Asymmetric changes in dopamine and serotonin in the mPFC and amygdala are associated with individual differences in ethanol self-administration in rats, suggesting that differences in post-withdrawal amygdala neurochemistry contribute to differences in ethanol consumption (Carlson & Drew Stevens, 2006). It has been reported that vasopressin/V(1b) R signaling in the BLA control the transition to excessive drinking in ethanol dependent rats (Edwards, Guerrero, Ghoneim, Roberts, & Koob, 2012). The AP-1 transcription factor and ERK signaling pathway have been shown to be activated by discrete alcohol-associated cues in both the BLA and CeA in studies of the reinstatement of alcohol seeking. Immunocytochemical analyses showed that Fos activation was produced by reexposure to ethanol-associated contextual cues in the BLA and CeA. However, the activation of Jun and the ERK signaling pathway produced by reexposure to ethanol-associated contextual cues was only found in the BLA. Molecular and neural activity in the BLA and CeA may be mechanisms that underlie alcohol-seeking behavior induced by discrete cues (Radwanska et al., 2008). Comparisons of two F1 hybrid strains of mice, which exhibit ethanol intake in an experience-dependent manner, showed that activation of the inducible transcription factor DFosB is positively correlated with ethanol preference and intake in reward-, aversion- and stress-related brain regions, including the amygdala (Ozburn et al., 2012). Glutamate neurotransmission plays a critical role in cue-induced relapse-like behavior. Systemic administration of a selective mGluR2/3 agonist can prevent the reinstatement of alcohol-seeking behavior, and ethanol-dependent rats are more sensitive to this effect. Additionally, these effects were accompanied by the modulation of c-fos expression in many brain subregions, including the amygdala (Kufahl, Martin-Fardon, & Weiss, 2011; Zhao et al., 2006). NMDA/glycine receptor antagonist blocks the cannabinoid-induced relapse-like drinking, which may be associated with the altered expression of NMDA subunits genes in the amygdala (Alen et al., 2009). Using glutamate oxidase (GluOx)coated biosensors to monitor changes in extracellular glutamate in specific brain regions, neuronal activity and glutamatergic transmission in the BLA and NAc were shown to increase during cue-induced reinstatement of alcohol-seeking behavior (Gass, Sinclair, Cleva, Widholm, & Olive, 2011). Furthermore, pretest injections of the selective mGluR5 antagonist MTEP into the BLA or NAc eliminate the cue-induced reinstatement of alcohol seeking (Sinclair, Cleva, Hood, Olive, & Gass, 2012). These findings suggest that glutamatergic activity in the BLA and NAc is required for alcoholseeking behavior. Finally, a recent study demonstrated that mGluR2/3 in the amygdala plays a functional role in the modulation of the expression of the discriminative stimulus effects of alcohol (Cannady, Grondin, Fisher, Hodge, & Besheer, 2011). Dynorphin/j-opioid receptor (KOR) systems in the extended amygdala appear to be a primary mediator of negative

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reinforcement learning in alcohol-dependent animals and the effects of chronic stress on alcohol reward and seeking behaviors (Walker, 2012; Walker, Valdez, McLaughlin, & Bakalkin, 2012). It has been found that corticosteroid-dependent plasticity in the CeA mediates the compulsive alcohol drinking behaviors in rats (Vendruscolo et al., 2012). Additionally, systemic administration of the opioid receptor antagonist naltrexone can attenuate context-induced alcohol seeking and inhibit c-fos mRNA expression in the lateral amygdala and CA3 subregion of the hippocampus (Marinelli, Funk, Juzytsch, Li, & Le, 2007). Furthermore, pretest injections of naloxone methiodide into the BLA but not dorsal hippocampus dose-dependently suppress context-induced reinstatement (Marinelli, Funk, Juzytsch, & Le, 2010). These studies suggest that opioid transmission in the BLA plays an important role in context-induced alcohol seeking. Alcohol exposure has immediate and prolonged effects on the hypothalamic–pituitary–adrenal (HPA) axis and CeA, likely by directly modulating corticotropinreleasing factor (CRF) or brain catecholamine levels (Allen, Lee, Koob, & Rivier, 2011). Although activation of the HPA axis may facilitate the reinforcing effects of alcohol during initial drug use, overactivation of the HPA axis may lead to the sensitization of brain stress systems and further drive escalated and compulsive drug intake via negative reinforcement. Neuropeptide Y blocks the transition to alcohol dependence by suppressing GABAergic transmission in the CeA through actions at presynaptic Y2 receptors (Gilpin et al., 2011). A history of stress increases PDE10A mRNA levels in the BLA and plPFC and drives heightened alcohol intake and preference in susceptible individuals (Logrip & Zorrilla, 2012). These studies indicate that neuroendocrine stress systems play an important role in alcohol dependence. Infusion of the GR antagonist mifepristone systemically or into the CeA but not BLA suppresses the yohimbine-induced reinstatement of ethanol seeking (Simms, Haass-Koffler, Bito-Onon, Li, & Bartlett, 2012), confirming that the GR system in the CeA plays an important role in the development of ethanol dependence and may represent a potential pharmacological target for the treatment of alcoholism. Interactions among glutamate, GABA, cholinergic and dopamine neurotransmitter systems within the VTA, CeA and PFC have been implicated in nicotine addiction using animal models in preclinical studies (Markou, 2008). Endocannabinoid signaling in the BLA has also been shown to play a critical role in conditioned nicotine seeking in an animal model of nicotine self-administration (Kodas, Cohen, Louis, & Griebel, 2007; Yamada & Bruijnzeel, 2011). Intra-BLA infusion of the cannabinoid CB1 receptor antagonist rimonabant markedly reduces conditioned nicotine-seeking behavior, without affecting spontaneous locomotor activity in a conditioned cue-induced nicotine-seeking test after 1 month of withdrawal from nicotine self-administration, suggesting that endocannabinoid transmission in the BLA contributes to conditioned nicotine-seeking behavior (Kodas et al., 2007). Intra-CeA infusion of the a2-adrenergic receptor agonists clonidine and dexmedetomidine significantly attenuates nicotine-seeking behavior reinstated by footshock. These results indicate that noradrenergic mechanisms in the CeA at least partially underlie the reinstatement of nicotine seeking induced by stress and that a2-adrenergic receptors may be a potential target for the treatment of tobacco addiction in humans (Yamada & Bruijnzeel, 2011) (see Table 2). 4. Concluding remarks We reviewed studies that focused on the role of the amygdala in drug-related memories assessed in rodent CPP and self-administration models. The main conclusion that may be drawn from such studies is that the amygdala plays a pivotal role in both structural and functional neuroadaptations that underlie drug-related memories and depend on the specific memory phase, including

acquisition, consolidation, retrieval, reconsolidation and extinction, and types of abused drugs (e.g., opiates, cocaine, nicotine and alcohol). Drug-related memories that usurp normal neural learning and memory processes have been considered to contribute to the persistence of drug use and relapse to compulsive drug seeking when human addicts or abstinent animals are reexposed to previously drug-paired cues (Hyman, Malenka, & Nestler, 2006; Nestler, 2001; Robbins et al., 2008). Disruption of drug memory may be a promising prospects for treatment of addiction. From the perspective of anatomical structures, the amygdala has intricate bidirectional connections to the PFC (Ghashghaei & Barbas, 2002; Ghashghaei et al., 2007; Wise, 2008) and mesolimbic system (Brog et al., 1993; Groenewegen et al., 1990), including the NAc, which is activated when craving occurs in cocaine addicts and is involved in aspects of emotional responses and reinforcement learning (Bonson et al., 2002; Breiter et al., 1997; Childress et al., 1999; Fig. 1). The amygdala encodes emotionally conditioned stimulus information and has been shown to play distinct roles in various phases of drug-related memory in self-administration and CPP studies. Although the method of acquiring abused drugs may differ in self-administration and CPP paradigms, both models simulate the establishment of drug-related memories through repeated training. As reviewed above, various molecules and pathways in the amygdala are involved in different phases of drug-related memory, suggesting that the amygdala plays a functional role in the control of drug-related memory. Specific mechanisms in the amygdala that underlie drug-related memory process, revealed by both CPP and self-administration studies, include Cdk5, the PKC signaling pathway, the ERK signaling pathway, CaMKII, the noradrenergic system, the cholinergic system, the mesolimbic dopamine system, the glutamate system and stress systems (Bernardi et al., 2009; Li et al., 2008, 2010; Lu et al., 2005; Rezayof et al., 2002; Schroeder & Packard, 2002; Zarrindast et al., 2004, 2005). Considering the limitations of the CPP model, such as passive drug delivery and fixed drug doses delivered, the self-administration model may be superior with regard to simulating specific characteristics of addiction. Self-administration studies in animals support the pivotal role of the amygdala in mediating conditioned cue- and drug-induced drug-seeking behavior. For example, disruption of the reconsolidation of drug-related memories can attenuate the cue-induced maintenance of and relapse to cocaine seeking (Lee et al., 2005; Miller & Marshall, 2005b). In a second-order schedule of reinforcement, blockade of the reconsolidation of drug-related memories attenuates drugseeking behavior. However, the BLA also plays distinct roles in learning cocaine- and opiate-stimulus associations, such as the differential effects of amygdala lesions on the acquisition of heroin and cocaine self-administration (Alderson et al., 2000). In addition to data from rodent research, the amygdala is activated when cocaine addicts are exposure to cocaine-related cues (Ciccocioppo et al., 2001; Grant et al., 1996; Kilts et al., 2001). Thus, we conclude that the amygdala is a key region for encoding conditioned learning associated with drugs of abuse and that the amygdala may be an important manipulation target to disrupt drug memory. The conditioned reinforcing effects of drugs of abuse include both positive and negative aspects. In both preclinical and clinical researches (O’Brien, Childress, McLellan, & Ehrman, 1992), the process of conditioned learning has been recognized to contribute to the development and maintenance of addictive behaviors. The amygdala is considered as a primary region that encodes conditioned stimulus information, including both aversive and appetitive emotionally conditioned stimulus learning (Everitt et al., 2003). Reinforcement learning is a process by which sensory stimuli become associated with positive or negative value. The amygdala subserves incentive learning and as a whole controls both the associative significance (through Pavlovian incentive learning)

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Y.-X. Luo et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx Table 2 Role of amygdala in drug memories assessed by self-administration model. Brain region

Main findings

Strain/sex

Reference

BLA

The BLA is involved in the process of cocaine cue-elicited seeking behavior

Kufahl et al. (2009)

BLA

Disrupted drug memory reconsolidation reduces cocaine seeking and relapse

Male Sprague– Dawley rats Male ListerHooded rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Wistar rats

BLA BLA BLA Rostral BLA and plPFC

+

Na channel-mediated mechanisms mediate the consolidation of both reward and extinction learning Reversible inactivation of the BLA or CeA produces differential affects on the acquisition and expression of drug memory Reinstatement of cue-induced cocaine seeking requires the BLA

Caudal BLA and rostral BLA BLA

Interaction between the rostral BLA and plPFC regulates the reinstatement of cocaine-seeking behavior D1 receptors in the caudal and rostral BLA mediate cocaine seeking during different phases of the development of addiction The control drug seeking by conditioned reinforcers depends on D3 receptors

CeA

D2/D3 receptors are sufficient to modulate cocaine-cues and cocaine priming

BLA

D1 receptors underlie the reinstatement of cue-induced cocaine-seeking behavior

BLA

Drug memory reconsolidation blockade occurs via modulation of glutamatergic transmission

BLA

Disruption of the reconsolidation of drug memories reduces cocaine-seeking behavior

CeA

mGluR2/3 agonist attenuates the incubation of cocaine craving

CeA

ERK signaling pathway mediates the incubation of cocaine-seeking behavior

BLA

NMDA receptor blockade disrupts the consolidation of reward memory and extinction learning

BLA and DH

The BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories The amygdala needs to be functionally active simultaneously in at least one brain hemisphere for acquisition of cocaine cue extinction learning Reconsolidation of a cocaine-paired stimulus critically depends on PKA in the amygdala

Rostral BLA Amygdala BLA BLA

Contextual drug-memory reconsolidation in Pavlovian and instrumental settings involves distinct neuroanatomical mechanisms Neural activity mediates heroin-associated cue- and heroin-induced reinstatement

BLA

The BLA is not necessary for the acquisition of opiate-stimulus associations

BLA

Amygdala BLA

The disruption of the reconsolidation of withdrawal memories reduces the suppression of seeking behavior The amygdala may be a critical component of the neural circuitry that underlies the aversive emotional consequences of drug withdrawal mGlu2R attenuates stress- and cue-induced ethanol seeking mGlu2R and adrenergic systems control the stress-induced reinstatement of nicotine seeking

CeA

Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats

BLA

mGluR5 receptors in the BLA and NAc mediate the cue-induced reinstatement of ethanolseeking behavior NPY modulates GABAergic signaling in the CeA and blocks the transition to alcohol dependence Vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats Opioid receptors in the BLA mediate context-induced alcohol seeking

Amygdala

CeA BLA BLA BLA, ACC, hypothalamus, and striatum CeA

Cannabinoid-induced increase in relapse-like drinking is prevented by blockade of the glycinebinding site of NMDA receptors Mifepristone in the CeA reduces the yohimbine stress-induced reinstatement of ethanolseeking.

Male Wistar rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Lister Hooded rat Male Lister Hooded rat Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Wistar rats

Lee et al. (2006) Fuchs et al. (2006) Kruzich and See (2001) Gabriele and See (2010) Mashhoon et al. (2010) Mashhoon et al. (2009) Di Ciano (2008) Thiel et al. (2010) See et al. (2001) Milton et al. (2008) Lee et al. (2005) Lu et al. (2007) Lu et al. (2004) Feltenstein and See (2007) Wells et al. (2011) Szalay et al. (2011)

Male Sprague– Dawley rats Male Sprague– Dawley rats Male Sprague– Dawley rats Male Lister Hooded rats Male Lister Hooded rats Male Fisher rats

Sanchez et al. (2010) Wells et al. (2012)

Male Wistar rats Male Wistar rats

Zhao et al. (2006) Yamada and Bruijnzeel (2011) Vendruscolo et al. (2012) Sinclair et al. (2012)

Adult male Wistar rats Male Wistar rats Male Wistar rats Male Wistar rats Male Wistar rats Male Wistar rats Male Long-Evans rats

Fuchs and See (2002) Alderson et al. (2000) Hellemans et al. (2006) Zhou et al. (2008)

Gilpin et al. (2011) Edwards et al. (2012) Marinelli et al. (2010) Alen et al. (2009) Simms et al. (2012)

BLA, basolateral amygdala; CeA, central nucleus of the amygdala; NAc, nucleus accumbens; VTA, ventral tegmental area; PFC, prefrontal cortex; plPFC, prelimbic prefrontal cortex; DH, dorsal hippocampus; ACC, anterior cingulate cortex; NMDA, N-methyl-D-aspartate; GABA, c-aminobutyric acid; D1, dopamine 1; D2, dopamine 2; ERK, extracellular signal-regulated kinase; mGluR, metabotropic glutamate receptor; PKA, protein kinase A.

and reward value (through instrumental incentive learning) of sensory-perceptual events. Although the amygdala is well known to be important for processing drug memory, further studies will be needed to functionally identify the cellular/molecular alterations that occur in different phases of both drug reward-associated

memories and aversive memories associated with drug withdrawal to promote memory-based treatments for addiction. Additionally, how dynamic interactions between the amygdala and other brain structures with which it is connected support a wide range of emotional behaviors needs to be clarified.

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Fig. 1. Schematic diagram of a neural network that illustrates the role of the amygdala in drug memory. The main interactions between the amygdala and the brain structures with which it is connected underly associative learning processes to contribute to addictive behavior output. BLA, basolateral amygdala; CeA, central nucleus of the amygdala; VTA, ventral tegmental area; SN, substantia nigra; DA, dopamine; NAc, nucleus accumbens; CS, conditioned stimulus; US, unconditioned stimulus.

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Please cite this article in press as: Luo, Y.-X., et al. Role of amygdala in drug memory. Neurobiology of Learning and Memory (2013), http://dx.doi.org/ 10.1016/j.nlm.2013.06.017