Role of corticostriatal circuits in context-induced reinstatement of drug seeking

Available online at www.sciencedirect.com

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b r a i n r e s e a r c h ] ( ] ] ] ] ) ] ] ] – ] ] ]

http://dx.doi.org/100006-8993/Published

Abbreviations: BLA

accumbens core; CA3

cortex; dlStr, dorso

putamen; dmStr, d

dSub, dorsal subicu

accumbens shell; AP

CART, Cocaine and

receptor antagonist);

6981, NR2B subunit

antagonist; LY379268nCorresponding anCorresponding aE-mail addresses

Please cite thisdrug seeking. Bra

Research Report

Role of corticostriatal circuits in context-inducedreinstatement of drug seeking

Nathan J. Marchanta,b,n, Konstantin Kaganovskya, Yavin Shahama,Jennifer M. Bosserta,n

aBehavioral Neuroscience Branch, IRP, NIDA, Baltimore, MD, USAbFlorey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, VIC, Australia

a r t i c l e i n f o

Article history:

Accepted 1 September 2014

Drug addiction is characterized by persistent relapse vulnerability during abstinence. In absti-

nent drug users, relapse is often precipitated by re-exposure to environmental contexts that

Keywords:

Abstinence

Alcohol

Cocaine

Context

Craving

Cue

Extinction

Drug self-administration

Heroin

Punishment

Reinstatement

Relapse

Review

.1016/j.brainres.2014.09.00by Elsevier B.V.

, basolateral amygdale;

, field CA3 of the hippoc

lateral striatium; pDHipp,

orsomedial striatum; VHip

lum; vSub, ventral subic

5, NMDA receptor antag

Amphetamine Regulated

CNQX, AMPA/kainate re

-containing NMDAR antag

, mGluR2/3 agonist; TTXuthor at: Behavioral Neuuthor.: [email protected]

article as: Marchant,in Research (2014), htt

a b s t r a c t

were previously associated with drug use. This clinical scenario is modeled in preclinical studies

using the context-induced reinstatement procedure, which is based on the ABA renewal

procedure. In these studies, context-induced reinstatement of drug seeking is reliably observed

in laboratory animals that were trained to self-administer drugs abused by humans.

In this review, we summarize neurobiological findings from preclinical studies that have

focused on the role of corticostriatal circuits in context-induced reinstatement of heroin,

cocaine, and alcohol seeking. We also discuss neurobiological similarities and differences in the

corticostriatal mechanisms of context-induced reinstatement across these drug classes. We

conclude by briefly discussing future directions in the study of context-induced relapse to drug

seeking in rat models. Our main conclusion from the studies reviewed is that there are both

similarities (accumbens shell, ventral hippocampus, and basolateral amygdala) and differences

(medial prefrontal cortex and its projections to accumbens) in the neural mechanisms of

context-induced reinstatement of cocaine, heroin, and alcohol seeking.

This article is part of a Special Issue entitled SI:Addiction circuits.

Published by Elsevier B.V.

4

mOFC, medial orbitofrontal cortex; CA1, field CA1 of the hippocampus; NAc Core, nucleus

ampus; NAc Shell, nucleus accumbens shell; DHipp, dorsal hippocampus; OFC, orbitofrontal

posterior dorsal hippocampus; dmPFC, dorsomedial prefrontal cortex; vCPu, ventral caudate

p, ventral hippocampus; dStriatum, dorsal striatum; vmPFC, ventromedial prefrontal cortex;

ulum; lOFC, lateral orbitofrontal cortex; VTA, ventral tegmental area; lShell, lateral nucleus

onist; MþB, MuscimolþBaclofen (GABAA and GABAB receptor agonists, respectively);

Transcript; Naloxone-methiodide, a charged analog of naloxone (a preferential mu opioid

ceptor antagonist; PP2, Src-family kinase inhibitor; CTAP, m-opioid receptor antagonist; Ro25-

onist; JNJ16259685, mGluR1-selective antagonist; SCH 23390, Dopamine D1-like receptor

, tetrodotoxin (tetrodotoxin-sensitive voltage-gated sodium channel blocker)roscience Branch, IRP, NIDA, Baltimore, MD, USA.

ov (N.J. Marchant), [email protected] (J.M. Bossert).

N.J., et al., Role of corticostriatal circuits in context-induced reinstatement ofp://dx.doi.org/10.1016/j.brainres.2014.09.004

http://dx.doi.org/10.1016/j.brainres.2014.09.004




mailto:[email protected]

mailto:[email protected]





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Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Role of corticostriatal inputs in context-induced reinstatement of drug seeking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2.1. Heroin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2. Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.3. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

3. Comparison of corticostriatal inputs in context-induced reinstatement across drug classes. . . . . . . . . . . . . . . . . . . . . . 84. Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1. Introduction

Drug addiction is characterized by persistent relapse vulner-ability during abstinence (Hunt et al., 1971; O'Brien, 2005).This relapse is a defining feature of drug addiction and a majorimpediment to successful treatment (Sinha et al., 2011) (Box 1).In abstinent drug users, relapse is often precipitated by re-exposure to environmental contexts that are associated withdrug use (O'Brien et al., 1992) (Box 1). This clinical scenario ismodeled in preclinical studies using a context-induced reinstate-ment procedure (Crombag and Shaham, 2002; Crombag et al.,2008), which is based on the ABA renewal procedure (Boutonand Bolles, 1979; Nakajima et al., 2000) (Box 1). In thisprocedure, laboratory animals are initially trained to self-administer a drug in a specific environmental context (con-text A). Following self-administration training, drug seekingis extinguished through non-reinforcement in an alternative,distinct, environmental context (context B). The contextstypically differ in their auditory, visual, tactile, olfactory,and circadian properties. After repeated extinction sessions,drug seeking is extinguished and the laboratory animal isthen tested, in extinction conditions, for context-inducedreinstatement in the original training context. The opera-tional definition of reinstatement in this procedure is signifi-cantly higher non-reinforced operant responding in theoriginal training context A as compared to the extinctioncontext B (Box 1). Since the initial demonstration with speed-ball (a heroin–cocaine combination) (Crombag and Shaham,2002), context-induced reinstatement of extinguished drugseeking has been observed with several major drugs of abuse(Crombag et al., 2008), including heroin (Bossert et al., 2004),cocaine (Crombag et al., 2002), alcohol (Burattini et al., 2006),and nicotine (Diergaarde et al., 2008).

In line with the aims of this special edition of BrainResearch, in this review we summarize neurobiological find-ings from preclinical studies that have focused on the role ofcortical and corticostriatal circuits in context-induced rein-statement of drug seeking. During the last twelve years,many studies indicate a role of several corticostriatal projec-tions in context-induced reinstatement of drug seeking(Bossert et al., 2013). Below, we discuss these neurobiologicalfindings separately for heroin, cocaine, and alcohol (seeTable 1 for summary of findings). In addition to corticostriatalpathways, we also discuss the role of ventral tegmental area(VTA) in context-induced reinstatement of drug seeking,because dopamine (Fallon and Moore, 1978) and glutamate(Yamaguchi et al., 2007, 2011) neurons in this brain region

Please cite this article as: Marchant, N.J., et al., Role of codrug seeking. Brain Research (2014), http://dx.doi.org/10.1016/j.b

project to the different corticostriatal areas that are coveredin our review.

Note that although there are published studies on context-induced reinstatement of nicotine or methamphetamineseeking (Diergaarde et al., 2008; Widholm et al., 2011; Wingand Shoaib, 2008), we do not include these studies in ourreview because these studies only assessed the effect ofsystemic drug injections on context-induced reinstatement.We also do not review studies on relapse to drug seeking afterperiods of abstinence (e.g., incubation of cocaine craving) inwhich a single extinction session in the presence of con-textual drug cues (the self-administration chamber) anddiscrete drug infusion cues (tone, light) is used to assessrelapse to drug seeking (Fuchs et al., 2006; Marchant et al.,2013b; Pickens et al., 2011). We exclude these studies, becausewe and others have shown that responding in the extinctiontests used to study relapse after abstinence is context-independent (Crombag et al., 2008).

2. Role of corticostriatal inputs in context-induced reinstatement of drug seeking

2.1. Heroin

The first preclinical reinstatement study on heroin-priming-induced reinstatement of heroin seeking was published in1983 (de Wit and Stewart, 1983). Since then, several labs haveinvestigated mechanisms of reinstatement of heroin seekinginduced by heroin priming, stress, and discrete cues (Bossertet al., 2013; Shaham et al., 2000; Shalev et al., 2002). It hasbeen known for many years that environmental contextsassociated with use of heroin, and other opiates, plays acritical role in relapse during abstinence (Robins et al., 1974;Wikler, 1973). Therefore, a decade ago we began a series ofstudies on the neurobiological substrates of context-inducedreinstatement of heroin seeking. Based on Bouton's researchand theoretical writing (Bouton and Swartzentruber, 1991;Bouton, 2002), and our initial study with speedball (a heroin–cocaine combination) (Crombag and Shaham, 2002), ouroriginal intention was to study mechanisms underlying theoccasion setter's properties of the drug-associated context, orthe ability of the context to ‘renew’ the conditioned responseto the discrete cue (compound tone-light) previously pairedwith heroin injections after extinction of the response tothese cues in a non-drug context (Box 1).

rticostriatal circuits in context-induced reinstatement ofrainres.2014.09.004




Box 1–Glossary of terms.Asymmetrical disconnection procedure (also called the“asymmetric” lesion/inactivation procedure: (Gold,1966): In this procedure the role of a neuronal pathwayin a given behavior is inferred from the observation thatlesion (permanent or reversible) or receptor blockade ofone brain site in one hemisphere, together with lesion/receptor blockade of a second brain site in the contral-ateral hemisphere, disrupts the behavior of interest(Gaffan et al., 1993; Setlow et al., 2002). Basic assump-tions in “disconnection” studies are that the targetbehavior is at least partially intact following ipsilaterallesion/inactivation of the two brain sites in the samehemisphere and that neuronal projections are exclu-sively or primarily ipsilateral.

Contexts: Refers to a configuration of diffuse cuesproviding the background setting of learning. Investigationson context effects in learning indicate that many stimulican function as contexts, including external cues likesmells and physical environments, interceptive drug states,mood or hormonal states, and time of day (Bouton, 1993).

Context-induced reinstatement: Laboratory animals arefirst trained to self-administer a drug in an environment(termed context A) associated with a specific set of“background” stimuli (e.g., operant chamber fan, time ofday, visual cues, tactile cues, and olfactory cues). Leverpressing is then extinguished in a different environment(termed context B) with a different set of “background”stimuli. During reinstatement testing under extinctionconditions, exposure to context A previously paired withthe drug reinstates operant responding. The procedureis based on a “renewal” procedure that has been used toassess the role of contexts in resumption of conditionedresponses to aversive and appetitive cues after extinc-tion (Bouton and Swartzentruber, 1991). Note that thereare two versions of context-induced reinstatement: (1)Discrete drug cues are present during training, extinc-tion, and reinstatement (Crombag and Shaham, 2002); inthis procedure, contexts may indirectly induce drugseeking by modulating the effects of discrete infusioncues on drug seeking by serving as occasion setters. (2)Discrete cues are absent during training, extinction, andreinstatement (Fuchs et al., 2005); in this procedure,contexts may directly induce drug seeking by acquiringPavlovian conditioned stimulus properties.

Context-induced relapse after punishment: This procedureis similar to context-induced reinstatement with theexception that in context B pressing the active lever resultsin drug delivery and footshock punishment. The footshockpunishment occurs at the same time as drug delivery, butonly 50% of reinforced lever presses are punished. Drugseeking remains suppressed in the punishment context (B),but renews during the relapse tests in the drug context (A)(Marchant et al., 2013a, 2013b, 2014).

Daun02 inactivation procedure: A method to selectivelydisrupt the function of behaviorally activated neurons.This method enables investigation of whether “neuronalensembles” (subsets of activated neurons) are involved

in particular behaviors. Selective inactivation is per-formed by injecting a prodrug, Daun02 into the brains ofc-fos-lacZ transgenic rats that express beta-galactosi-dase in strongly activated neurons. Beta-galactosidaseconverts Daun02 into daunorubicin, which reducesneuronal excitability (Koya et al., 2009; Cruz et al., 2013).

Discrete cue-induced reinstatement: Laboratory animalsare first trained to self-administer a drug; each drugdelivery is temporally paired with a discrete cue (e.g.,tone, light). Lever pressing is then extinguished in theabsence of the drug and the cue. During reinstatementtesting, exposure to the discrete cue, which is earnedcontingently during testing, reinstates operant respond-ing (Meil and See, 1996b).

Discriminative cue-induced reinstatement: Laboratoryanimals are trained to self-administer a drug in thepresence of distinct discriminative stimuli (e.g., visualcues, olfactory cues); one set of stimuli signals drugavailability (Sþ) and the other signals unavailability(S� ). Lever pressing is then extinguished in the absenceof the discriminative stimuli and the drug. During thereinstatement test, re-exposure to the Sþ, but not S� ,reinstates operant responding (Weiss et al., 2000).

Occasion setter cue: In Pavlovian conditioning occasionsetter cues signal whether another conditioned cue (CS) isto be reinforced or not reinforced. In contrast to traditionalexcitatory of inhibitory Pavlovian CSs, occasion setter cuestypically do not affect behavior directly but modulatebehavior elicited by other Pavlovian CSs (Holland, 1992).

Reinstatement: In the learning literature, reinstate-ment refers to the recovery of a learned response (e.g.,lever-pressing behavior) that occurs when a subject isexposed non-contingently to the unconditioned stimu-lus (e.g., food) after extinction (Bouton andSwartzentruber, 1991). In studies of reinstatement ofdrug-seeking, reinstatement typically refers to theresumption of drug seeking after extinction followingexposure to drug priming (de Wit and Stewart, 1981; Selfet al., 1996; Spealman et al., 1999), different types of drugcues (Crombag and Shaham, 2002; Meil and See, 1996a;Weiss et al., 2000), or different stressors (Shaham andStewart, 1995; Shalev et al., 2001).

Relapse: A term used to describe the resumption ofdrug-taking behavior during self-imposed or forcedabstinence in humans (Wikler, 1973).

Renewal: Refers to the recovery of extinguishedconditioned behavior that can occur when the contextis changed after extinction; renewal often occurs whenthe subject returns to the learning (training) environ-ment after extinction of the conditioned response in adifferent environment (Bouton and Swartzentruber,1991).

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We initially assessed the effect of systemic injectionsof LY379268, a group II metabotropic glutamate receptor(mGluR2/3) agonist which acts centrally to decrease evokedglutamate release (Schoepp, 2001), on context-induced rein-statement of heroin seeking (Bossert et al., 2004). We usedLY379268 because previous studies found that systemic





Table 1 – Effect of intracranial injections of pharmacological agents on context-induced reinstatement of drug seeking.“↓”refers to a decrease in context-induced drug seeking (in the training context where drug was available) due to themanipulation, “—”refers to no effect on context-induced drug seeking due to the manipulation.

Heroin Cocaine Alcohol References

dmPFC MþB — TTX ↓ MþB ↓ Bossert et al. (2011) Fuchs et al. (2005), Willcocksand McNally (2012)

vmPFC MþB ↓ Daun02Inactivation ↓

TTX — MþB — Bossert et al. (2011), Fuchs et al. (2005), Willcocksand McNally (2012)

BLA TTX ↓ Naloxone-methiodide↓

Fuchs et al. (2005), Marinelli et al. (2010)

DHipp TTX ↓ Fuchs et al. (2005) Lasseter et al. (2010), Luo et al.(2011), Xie et al. (2010, 2013, 2014)AP5, PP2, or Ro25-6981

↓

JNJ16259685 ↓

SCH 23390 ↓

MþB↓[CA3]MþB — [pDHipp]

NAc core LY379268 — MþB ↓ SCH 23390 ↓ Bossert et al. (2006a, 2007), Chaudhri et al. (2009),Cruz et al. (2014), Fuchs et al. (2008), Xie et al. (2012)SCH 23390 — JNJ16259685 or CNQX

↓

Daun02 Inactivation—

NAc shell LY379268 ↓ MþB ↓ SCH 23390 ↓ Bossert et al. (2006a, 2007); Chaudhri et al.( 2009)Cruz et al. (2014) Fuchs et al. (2008), Millan andMcNally (2012), Perry and McNally (2013), Xie et al.(2012)

SCH 23390 ↓ CNQX ↓ CART ↓

JNJ16259685 — CTAP ↓

Daun02 Inactivation ↓

dStriatum LY379268 — MþB [dlStr] ↓ Bossert et al. (2006a, 2009), Fuchs et al. (2006), Xieet al. (2012)SCH 23390 ↓ CNQX —

JNJ16259685 —

VTA LY379268 ↓ Bossert et al. (2004)OFC MþB↓[lOFC not

mOFC] SCH23390↓[lOFC]

Lasseter et al. (2009, 2014)

VHipp MþB ↓ MþB ↓ Bossert and Stern (2014), Lasseter et al. (2010)OFC–BLA Ipsilateral or

contralateral MþB ↓

Lasseter et al. (2011, 2014)

SCH 23390 in OFC andMþB in ipsilateral orcontralateral BLA ↓

BLA–

DHippContralateral MþB ↓ Fuchs et al. (2007)

BLA–

dmPFCIpsilateral MþB ↓ Fuchs et al. (2007)Contralateral MþB ↓

vmPFC–NAc shell

MþB in vmPFC and SCH23390 in contralateral oripsilateral NAc Shell ↓

Bossert et al. (2012)

dlStr–NAcshell

Contralateral SCH 23390—

Bossert et al. (2009)

LS–VTA Contralateral MþB ↓ Luo et al. (2011)

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injections of LY379268 or other mGluR2/3 agonists decreaseseveral behavioral effects of drugs of abuse, including opiatewithdrawal symptoms (Vandergriff and Rasmussen, 1999)and discriminative cue-induced reinstatement of cocaine seeking(Baptista et al., 2004) (Box 1). We found that systemic injec-tions of LY379268 dose-dependently decrease context-induced reinstatement of heroin seeking (Bossert et al.,2004) at doses that do not affect heroin self-administration(Bossert et al., 2005) or high rates of responding for a sucrosesolution (Bossert et al., 2006b). We then examined the role ofmGluR2/3 in VTA, the cell body region of the mesolimbicdopamine system, because this brain area is involved in


opiate reward and reinstatement (Stewart, 1984; Wise, 1989)and dopaminergic output from VTA is controlled in part byglutamate afferents from several brain areas (Sesack et al.,2003). We found that injections of LY379268 into VTA, but notsubstantia nigra, decrease context-induced reinstatement ofheroin seeking (Bossert et al., 2004); however, this decreasewas partial and not dose-dependent.

Based on this finding, we then studied the effect ofLY379268 injections into nucleus accumbens, a terminalregion of the mesolimbic dopamine system and an area thatreceives glutamatergic input from several brain regions (Broget al., 1993; Groenewegen et al., 1999). We found that injections of





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LY379268 into medial accumbens shell decrease context-inducedreinstatement of heroin seeking (Bossert et al., 2006a). Injectionsinto accumbens core also decrease this reinstatement but only atdoses 3–10 times higher than that required in the accumbensshell, suggesting that the higher effective dose in the core wasdue to diffusion to the shell. None of the doses tested in dorsalstriatum were effective.

VTA and accumbens shell are the respective cell body andterminal regions of the mesolimbic dopamine system (Fallonand Moore, 1978). Thus, our findings suggest that the roleof glutamate in context-induced reinstatement involves mod-ulation of mesolimbic dopamine function. Indeed, early neu-roanatomical studies indicate that the cell body region of themesocorticolimbic dopamine system in the VTA plays acritical role in drug-induced reinstatement. Activation of thesemidbrain dopamine neurons by local morphine infusionsreinstates heroin seeking (Stewart, 1984) and systemic injec-tions of dopamine D1-like, D2-like, and mixed dopamineantagonists decrease heroin-priming induced reinstatement(Shaham and Stewart, 1996). Furthermore, McFarland andEttenberg (1997) found that the dopamine receptor antagonist,haloperidol, reduces runway time signaled by a heroin dis-criminative cue after being previously paired with a heroininjection. Additionally, local application of LY379268 reducesdopamine levels in accumbens shell, but not core (Greensladeand Mitchell, 2004), a finding that is highly relevant to ourresults.

We found that injections of the dopamine D1-like receptorantagonist SCH 23390 either systemically, or directly intomedial and lateral accumbens shell, but not core, decreasescontext-induced reinstatement of heroin seeking (Bossertet al., 2007). These data are consistent with findings that SCH23390 and a more selective dopamine D1 receptor antagonist,SCH 39166, decrease context- and discriminative-cue-inducedreinstatement of cocaine, alcohol, and sucrose seeking(Ciccocioppo et al., 2001; Crombag et al., 2002; Hamlin et al.,2007, 2008; Weiss et al., 2001) and that systemic SCH 23390injections decrease context-induced increases in Fos proteinexpression, a marker of neural activity (Morgan and Curran,1991), in accumbens shell (Hamlin et al., 2007, 2008). Thesedata are also in agreement with those of Ghitza et al. (2003)who found that re-exposure to discriminative cues that predictcocaine availability increases neuronal activity in accumbensshell but not core.

Because injections of SCH 23390 into accumbens shelldecrease context-induced reinstatement, our previous find-ing that LY379268 was effective in VTA is likely due todecreases in VTA dopamine transmission. This would thenresult in decreases in accumbens shell dopamine release and,consequently, less stimulation of local D1-family receptors.There is evidence that dopamine transmission in VTA ispartly controlled by excitatory glutamate projections fromseveral brain areas (Geisler et al., 2007) and based on electro-physiological and neuroanatomical studies (Manzoni andWilliams, 1999; Rouse et al., 2000), injections of LY379268into VTA should activate local presynaptic inhibitory mGluR2,resulting in decreased glutamate transmission, and conse-quently, decreased dopamine transmission.

We further characterized the role of striatal dopamine D1-like receptors and found that injections of SCH 23390 into


dorsolateral, but not dorsomedial, striatum decrease context-induced reinstatement (Bossert et al., 2009). These data areconsistent with those of Rogers et al. (2008) who reported thatreversible inactivation of dorsolateral striatum decreasesheroin priming- and discrete cue-induced reinstatement of heroinseeking (Box 1). We had previously found that injections ofSCH 23390 into lateral accumbens shell also decrease thisreinstatement. Since lateral shell neurons project directly tosubstantia nigra compacta (Usuda et al., 1998), which in turnproject to dorsal striatum (Beckstead et al., 1979), we used anasymmetric disconnection procedure (Gold, 1966) to examinewhether injections of SCH 23390 into one hemisphere ofdorsolateral striatum combined with injections of SCH23390 into the contralateral hemisphere of lateral accumbensshell would disrupt this reinstatement (Box 1). This manip-ulation had no effect on context-induced reinstatement ofheroin seeking, suggesting that D1-receptor-mediated dopa-mine transmission in dorsolateral striatum and lateralaccumbens shell are independently involved in this rein-statement (Bossert et al., 2009).

Our next question was which glutamatergic projection/s toaccumbens shell is/are involved in context-induced reinstate-ment of heroin seeking. Accumbens shell receives projectionsfrom medial prefrontal cortex (mPFC), thalamus, amygdala,and hippocampus (Groenewegen et al., 1999), and we foundthat re-exposure to the heroin context increases Fos proteinexpression in ventral mPFC and ventral subiculum/CA1(Bossert et al., 2011, 2012, unpublished findings). Subsequently,we found that reversible inactivation (using the GABAAþGABAB receptor agonist mixture muscimolþbaclofen) of ven-tral (comprised of ventral prelimbic and infralimbic cortex), butnot dorsal (comprised of dorsal prelimbic/anterior cingulate),mPFC decreases context-induced reinstatement of heroinseeking (Bossert et al., 2011). This effect was mimicked byselectively inactivating ventral mPFC Fos-activated neuronsusing the Daun02 inactivation method (Koya et al., 2009) (Box 1).We then asked whether the projections from ventral mPFC toaccumbens shell play a role in context-induced reinstatementand found that this reinstatement was associated withincreased Fos expression in ventral mPFC neurons that projectto accumbens shell, as assessed by double-labeling of Fos withFluorogold, a retrograde tracer (Bossert et al., 2012). Further-more, we confirmed the functional role of this projection incontext-induced reinstatement by demonstrating that reversi-ble inactivation of ventral mPFC in one hemisphere combinedwith dopamine D1 receptor blockade into contralateral oripsilateral accumbens shell decreases this reinstatement(Bossert et al., 2012). More recently, we also established afunctional role for ventral hippocampus in context-inducedreinstatement. We found that reversible inactivation of ventralsubiculum/CA1, but not dorsal subiculm/CA1, decreases thisreinstatement (Bossert and Stern, 2014). These data are alsoconsistent with our previous neurocircuitry findings, becauseventral subiculum/CA1 projects mainly to caudomedialaccumbens whereas dorsal subiculm/CA1 projects mainly torostrolateral accumbens (Groenewegen et al., 1987).

Taken together, we identified a role of glutamate trans-mission in VTA, dopamine transmission in dorsolateralstriatum, and both dopamine and glutamate transmissionin accumbens shell in context-induced reinstatement of





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heroin seeking (Bossert et al., 2004, 2006a, 2007, 2009). Wealso showed that projections from ventral mPFC to accum-bens shell are critical for this reinstatement (Bossert et al.,2012). We are currently exploring whether projections fromventral subiculum/CA1 to accumbens shell and projectionsfrom ventral subiculum/CA1 to ventral mPFC are critical forcontext-induced reinstatement of heroin seeking.

2.2. Cocaine

Early studies using the reinstatement procedure have indi-cated a role for mPFC, BLA, and accumbens core in discrimi-native- and discrete cue-induced reinstatement of cocaineseeking (Ciccocioppo et al., 2001; Fuchs et al., 2004;McLaughlin and See, 2003). Fuchs and colleagues initiallysought to determine whether or not brain areas controllingcue-induced reinstatement of cocaine seeking also controlcontext-induced reinstatement. They found that inactivation(using the sodium channel blocker tetrodotoxin) of dorsalmPFC and BLA, but not ventral mPFC or somatosensorycortex, decreases context-induced reinstatement of cocaineseeking (Fuchs et al., 2005). Because dorsal hippocampus isinvolved in contextual learning (Holland and Bouton, 1999),they tested whether this brain area also contributes tocontext-induced reinstatement. They found that inactivationof dorsal hippocampus decreases context- but not discretecue-induced reinstatement of cocaine seeking (Fuchs et al.,2005). This effect involves local dopamine and glutamatetransmission, because injections of dopamine D1-like,mGluR1, and NMDA receptor antagonists all decreasecontext-induced reinstatement (Xie et al., 2010, 2013, 2014).

In subsequent experiments, these authors found thatreversible inactivation (using muscimolþbaclofen) of bothaccumbens core and shell, and dorsolateral striatum,decreases context-induced reinstatement of cocaine seeking(Fuchs et al., 2006, 2008). Taken together, the findings ofFuchs et al. indicate that while some brain areas (BLA,accumbens core, dorsal mPFC) control both context- anddiscrete cue-induced reinstatement of cocaine seeking, otherbrain areas (accumbens shell, dorsal hippocampus) selec-tively control context-induced reinstatement.

Glutamate transmission in accumbens is critical for dis-crete cue-induced reinstatement of cocaine, heroin, nicotine,and alcohol seeking (Backstrom and Hyytia, 2007; Kumaresanet al., 2009; LaLumiere and Kalivas, 2008; Liechti et al., 2007;Sinclair et al., 2012). Based on this finding, Fuchs andcolleagues examined the contribution of specific glutamatereceptor subtypes in accumbens in context-induced rein-statement of cocaine seeking. They found that antagonismof mGluR1 (using JNJ16259685) in accumbens core, but notshell, decreases context-induced reinstatement of cocaineseeking (Xie et al., 2012); antagonism of AMPA/kainite gluta-mate receptors (using CNQX) in accumbens core and accum-bens shell decreases this reinstatement while injections intodorsal striatum were ineffective. The reasons why antagon-ism of mGluR1 receptors in core but not shell decreasescontext-induced reinstatement of cocaine seeking isunknown but may be related to distribution of the mGluR1receptor in these subregions. The involvement of accumbenscore in context-induced reinstatement of cocaine seeking is


supported by a recent study (Stankeviciute et al., 2013). Theseauthors reported that context-induced reinstatement is asso-ciated with a fast, transient increase in spine head diameterof accumbens core neurons. The functional significance ofthis finding and whether this effect also occurs in accumbensshell is unknown.

Bruce Hope and colleagues used the novel Daun02 method(Koya et al., 2009) to demonstrate that selective inactivationof Fos- and β-galactosidase-expressing neurons in accumbensshell but not core decreases context-induced reinstatementof cocaine seeking after these neurons were previouslyactivated by exposure to the cocaine-associated context afterextinction in the non-drug context (Cruz et al., 2014). Incontrast, Daun02 inactivation of neurons that were pre-viously activated by exposure to a novel context (whichincreases both Fos- and β-galactosidase-expression to levelshigher than the cocaine context) had no effect on subsequentcontext-induced reinstatement. These data are inconsistentwith the data from Fuchs and colleagues on the role ofaccumbens core in context-induced reinstatement (Fuchset al., 2008; Xie et al., 2012) (see above).

The reason for this discrepancy is not clear, but onepossibility is that unlike our studies (see Box 1), Fuchs et al.(2005) use a renewal procedure in which explicit drug-paireddiscrete cues are not present during drug self-administration(training), extinction, and reinstatement. This proceduraldifference is important, because the presence or absence ofdiscrete drug-paired cues can determine whether contextsdirectly induce drug seeking by acquiring Pavlovian condi-tioned stimulus properties or indirectly by modulating theeffects of discrete infusion cues on drug seeking by serving asoccasion setters (Holland, 1992; Rescorla et al., 1985; Urcelayand Miller, 2014). While these two mechanisms are notmutually exclusive (contexts may serve as both traditionalPavlovian conditioned stimuli and occasion setters), they arelikely mediated by different neurobiological substrates(Holland and Bouton, 1999). Such differences might accountfor some discrepancies between Fuchs' studies and the Cruzet al. (2014) study that includes explicitly-paired cues duringthe training, extinction, and reinstatement test phases.

Because dorsal mPFC, BLA, and dorsal hippocampus havereciprocal connections and project to accumbens (Cassell andWright, 1986; Sesack et al., 1989; Shinonaga et al., 1994), Fuchsand colleagues examined whether connections among thesestructures are critical for this reinstatement. Using an asym-metric disconnection procedure (Gold, 1966), they found thatcontralateral, but not ipsilateral, inactivation of BLA anddorsal hippocampus decreases context-induced reinstate-ment of cocaine seeking, whereas both contralateral andipsilateral inactivation of BLA–dorsal mPFC decreases thisreinstatement (Fuchs et al., 2007). These findings potentiallysuggest that a serial interaction exists between BLA anddorsal hippocampus, as well as BLA and dorsal mPFC, inmediating this reinstatement. However, this conclusionshould be taken with caution because of the similar effectsof contralateral and ipsilateral BLA–dorsal mPFC inactivation.

The asymmetrical disconnection procedure relies on thefact that most neuronal projections are ipsilateral and theassumption that most learned behaviors can be maintainedby an intact single hemisphere (but see (Christakou et al.,





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2005) for data inconsistent with this view). As such, the role aspecific projection plays in a given behavior is inferred fromthe manipulation of one brain area in one hemispheretogether with manipulation of a connected brain area in thecontralateral hemisphere (Gaffan et al., 1993). Therefore, amain requirement for interpreting results from asymmetricaldisconnection studies is that the target behavior remainslargely intact after ipsilateral lesion/inactivation of the twobrain areas (Setlow et al., 2002). As such, the result of Fuchset al. (2007) showing that that ipsilateral BLA–dorsal mPFCinactivation decreases reinstatement, suggests that the pro-jection is not critical for reinstatement. However, anatomicalstudies indicate reciprocal connections between these twostructures (McDonald, 1998; Pitkanen, 2000), including bilat-eral mPFC projections to amygdala (McDonald et al., 1996).Thus, the results of Fuchs et al. (2007) may not reflectindependence of the two brain areas in controlling context-induced reinstatement. Instead, they suggest that unilateralBLA–mPFC activity is not sufficient to maintain normalresponding for contexts during reinstatement testing.

BLA also shares reciprocal projections with orbitofrontalcortex (OFC) (Ghashghaei and Barbas, 2002). Inactivation oflateral, but not medial, OFC decreases context-induced rein-statement of cocaine seeking (Lasseter et al., 2009), an effectmimicked by contralateral and ipsilateral disconnection ofOFC–BLA projections (Lasseter et al., 2011). Similar to theprevious BLA–dorsal mPFC findings, one interpretation ofthese results is that bilateral input to these structures isrequired for normal responding during context-induced rein-statement tests, because lateral OFC shares reciprocal con-nections with BLA. An alternative interpretation is that athird brain area that projects to both structures is alsoinvolved in context-induced reinstatement.

A likely candidate is VTA since this brain area sendsdopaminergic projections to both BLA and OFC (Oades andHalliday, 1987). Potential support for this idea comes from thefinding that blocking dopamine D1-like receptors with SCH23390 in lateral OFC decreases context-induced reinstate-ment of cocaine seeking (Lasseter et al., 2014). This effect ismimicked by both contralateral and ipsilateral disconnectionof OFC from BLA and is reversed by combining the bilateralOFC SCH 23390 injections with the dopamine D1 agonist SKF81297. Additionally, the authors used unilateral retrogradetracer injections into OFC or BLA and found evidence forcontralateral projections from VTA to OFC, as well as con-tralateral projections from BLA to OFC and back to BLA fromOFC. Taken together, the authors proposed a role for VTA–OFC–BLA in context-induced reinstatement of cocaine seek-ing. Empirical support for this notion will require simulta-neous ‘disconnection’ of all three brain areas, which istechnically challenging.

In an elegant study, Luo et al. (2011) combined neuroana-tomical tracing, electrophysiology, and pharmacological dis-connection techniques to study the role of VTA–lateralseptum–dorsal hippocampus circuitry in context-inducedreinstatement of cocaine seeking. The authors first foundthat lateral septum modulates neuronal activity of the pro-jection from dorsal hippocampus CA3 to VTA. They thenfound that bilateral inactivation of dorsal hippocampus CA3decreases context-induced reinstatement of cocaine seeking,


an effect mimicked by disconnecting lateral septum andcontralateral, but not ipsilateral, VTA. Although the authorsdid not functionally disconnect this pathway (multi-synapticpharmacological disconnections that alter behavior are tech-nically challenging and difficult to interpret), their findingssuggest that neural transmission from dorsal hippocampusCA3 to VTA via lateral septum is a critical pathway forcontext-induced reinstatement of cocaine seeking.

Lastly, a critical role for ventral hippocampus has recentlybeen reported. Lasseter et al. (2010) found that inactivation ofventral hippocampus, but not posterior dorsal hippocampusor dentate gyrus, decreases context-induced reinstatement ofcocaine seeking. Based on previous findings that inactivationof anterior dorsal hippocampus decreases context-inducedreinstatement of cocaine seeking (Fuchs et al., 2005), thenegative finding of Lasseter et al. for posterior dorsal hippo-campus inactivation are unexpected.

Taken together, dopamine and glutamate transmission inseveral brain areas and circuits play a role in context-inducedreinstatement of cocaine seeking. These include the dorsalmPFC and lateral OFC along with their reciprocal connectionswith BLA (Fuchs et al., 2005, 2007; Lasseter et al., 2011, 2014).Striatal areas are also involved in this reinstatement, includ-ing dorsolateral striatum and accumbens shell and core(Fuchs et al., 2006, 2008; Xie et al., 2012). Finally, both ventraland dorsal hippocampus are involved in context-inducedreinstatement of cocaine seeking, and potentially a projectionfrom dorsal hippocampus to VTA via lateral septum (Fuchset al., 2007; Luo et al., 2011; Xie et al., 2010, 2013, 2014). Thereis also evidence for a role of the dopaminergic projectionfrom VTA to lateral OFC in context-induced reinstatement ofcocaine seeking (Lasseter et al., 2014).

2.3. Alcohol

Context-induced reinstatement of alcohol seeking was firstdemonstrated by Burattini et al. (2006). Since then, thisbehavioral effect has been replicated by several independentinvestigators (Bossert et al., 2013; McNally, 2014). To date,there are no studies directly implicating a corticostriatalprojection in mediating context-induced reinstatement ofalcohol seeking. However, several studies have examinedthe importance of striatal and cortical regions separately.

Nucleus accumbens shell is the main striatal sub-regionimplicated in context-induced reinstatement of alcohol seek-ing. Using Fos as a marker of neuronal activity, Hamlin et al.(2007) found that reinstatement of alcoholic beer seeking isassociated with increased Fos protein expression in accum-bens shell, as well as BLA, and lateral hypothalamus (LH).This effect is dependent on dopamine transmission: systemicinjections of the dopamine D1 receptor antagonist SCH 23390(10 mg/kg) block both context-induced reinstatement and Fosexpression in accumbens shell and LH, but not BLA. A criticalsite for the systemic effect of SCH 23390 is the accumbensshell. Chaudhri et al. (2009) found that SCH 23390 injectionsinto either accumbens shell or core decrease this reinstate-ment. Other pharmacological manipulations have also impli-cated the accumbens shell: local injections of Cocaine andAmphetamine Regulated Transcript (CART) (Millan andMcNally, 2012) and the m-opioid receptor antagonist CTAP





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(Perry and McNally, 2013) decrease context-induced reinstate-ment of alcohol seeking.

Chaudhri and colleagues have further described importantdifferences in the role of accumbens shell and core incontrolling cue- versus context-induced reinstatement. Asreviewed above, Chaudhri et al. (2009) showed that injectionsof SCH 23390 into either accumbens shell or core decreasescontext-induced reinstatement of alcohol seeking. In thisstudy, accumbens core was more sensitive to the lower dose(0.06 mg) than accumbens shell, which was only effective atthe highest dose tested (0.6 mg). In another study, Chaudhriet al. (2008) found that muscimolþbaclofen inactivation ofaccumbens core, but not shell, decreases context-inducedreinstatement of alcohol seeking. However, in this study therats were given a priming dose of ethanol in both theextinction and training contexts. As such, this importantprocedural difference might account for the negative effectof accumbens shell inactivation on alcohol seeking. Chaudhriet al. (2010) further showed the importance of ventral striatalsub-regions in cue-versus context-induced alcohol seekingusing a Pavlovian ABA renewal procedure in which a discretecue is paired with non-contingent alcohol delivery in onecontext, and the conditioned response to the discrete cue isextinguished in a different context. They found that eitheraccumbens core or shell inactivation (muscimolþbaclofen)decreases cue-induced conditioned responding in the originalcontext after Pavlovian extinction in an alternative context(i.e., renewal). However, when the alcohol-associated discretecue was presented in the extinction context, only accumbenscore inactivation decreased the conditioned response;accumbens shell inactivation had no effect. These findingsare consistent with the notion that accumbens core beingmore important for discrete cue-induced reinstatement ofdrug seeking whereas accumbens shell is more important forcontext-induced reinstatement.

The role of the projection from mPFC to striatum incontext-induced reinstatement of alcohol seeking has notbeen directly assessed using asymmetrical disconnection oroptogenetics. However, dorsal mPFC has been demonstratedto be a critical brain region. Willcocks and McNally (2012)used reversible inactivation (muscimolþbaclofen) to demon-strate that dorsal mPFC inactivation decreases context-induced reinstatement of alcohol seeking. Interestingly, therewas no effect of reversible inactivation of ventral mPFC, ordorsal peduncular cortex, located ventral to ventral mPFC. Todetermine which projections to accumbens shell are acti-vated during context-induced relapse, Hamlin et al. (2009)combined Fos expression with retrograde tracer (CTb) injec-tions into the accumbens shell. They found no reinstatement-associated increase of Fos expression in mPFC projections toaccumbens shell. Interestingly, the only projection that wasanalyzed and found significant was the midline thalamicstructure paraventricular thalamus (note that ventral subicu-lum was not analyzed in this study). This highlights thepotential importance of the glutamatergic inputs to the stria-tum from the thalamus, which is an often overlooked projec-tion. Finally, given that both accumbens core (Chaudhri et al.,2009) and dorsal mPFC (Willcocks and McNally, 2012) arecritical for context-induced reinstatement of alcohol seeking,it is possible that projections from dorsal mPFC to accumbens


core mediate context-induced reinstatement after extinction;however, to date there are no experimental data supportingthis hypothesis.

BLA is also important for context-induced reinstatementof alcohol seeking. Both Hamlin et al. (2007) and Marinelliet al. (2007) found increased Fos expression in BLA in ratstested for context-induced reinstatement. While Hamlin et al.(2007) found that blockade of D1-like receptors does notdecrease BLA Fos expression, Marinelli et al. (2007) foundthat systemic injections of the opioid receptor antagonistnaltrexone (1 mg/kg) attenuates both reinstatement and Fosexpression in BLA. A causal role for the opioid system incontext-induced reinstatement of alcohol seeking was sub-sequently demonstrated by Marinelli et al. (2010). They foundthat BLA injections of naloxone-methiodide ( a quaternarysalt of the preferential mu opioid receptor antagonist nalox-one) decrease context-induced reinstatement of alcoholseeking.

BLA sends dense projections to nucleus accumbens (Kelleyet al., 1982; McDonald, 1991). However, there is no evidence todate for a role of this projection in context-induced reinstate-ment. Millan and McNally (2011) performed an asymmetricaldisconnection experiment with BLA injections of musci-molþbaclofen and accumbens shell injections of the AMPAreceptor antagonist NBQX. They found that this manipulationinduces reinstatement of extinguished alcohol seeking. Thisfinding is consistent with previous results from this labshowing that bilateral accumbens shell injections of NBQXinduce reinstatement of extinguished alcohol seeking (Millanet al., 2010). Millan and McNally (2011) have also showed thatNBQX injections into accumbens shell do not decreasecontext-induced reinstatement of alcohol seeking, but doreinstate alcohol seeking in the extinction context B. Thisfinding suggests a possible dual role for BLA in controllingalcohol seeking. BLA is critical for promoting alcohol seekingin context-induced reinstatement, but it also suppressesalcohol seeking during extinction via projections toaccumbens shell.

In summary, like context-induced reinstatement ofcocaine and heroin seeking, the accumbens shell is a criticalneural substrate of context-induced reinstatement of alcoholseeking. BLA is also critical, and this is dependent on activityof opioid receptors in this brain area (Marinelli et al., 2010).The role of glutamate receptors in accumbens shell is morecomplicated. Glutamatergic inputs to accumbens shell fromthe midline thalamus are activated during context-inducedreinstatement (Hamlin et al., 2009), but a causal role of thisprojection has not been demonstrated. Projections from BLAto accumbens shell do not appear to play a role in context-induced reinstatement but appear important for suppressingalcohol seeking during extinction; this role is not contextdependent (Millan and McNally, 2011).

3. Comparison of corticostriatal inputs incontext-induced reinstatement across drug classes

As reviewed above, context-induced reinstatement of drug-seeking is reliably observed in laboratory animals that weretrained to self-administer drugs abused by humans. The





SNAdmPFC

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Manipulation of this brain area decreases context-induced reinstatement

Manipulation of this brain area does not alter context-induced reinstatement

Manipulation of this brain area has not been tested in context-induced reinstatement

Critical projections for context-induced reinstatement

Fig. 1 – Schematic illustrating the corticostriatal control ofcontext-induced reinstatement of heroin (A), cocaine (B), andalcohol (C) seeking. Inactivation of brain regions depicted inblack decreases context-induced reinstatement of therespective drug. Inactivation of brain regions depicted ingray has no effect on context-induced reinstatement of therespective drug. Brain regions depicted in white have notbeen tested for involvement in context-inducedreinstatement of the respective drug. Red arrows depictprojections that are critical for expression of context-induced reinstatement.

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robustness of this behavioral observation suggests a commonpsychological mechanism is responsible for context-inducedreinstatement (Crombag et al., 2008). However, despite theobserved behavior being identical (i.e. increased operantresponding during the reinstatement test), there is emergingevidence that the neural substrates of context-induced rein-statement across drug classes are not identical. In thissection we review the neurobiological similarities and differ-ences of the corticostriatal mechanisms of context-inducedreinstatement for heroin, cocaine, and alcohol seeking.

Nucleus accumbens shell stands out for being consistentlyimplicated in context-induced reinstatement across drug andnon-drug rewards. Increased Fos in accumbens shell isassociated with context-induced reinstatement of sucrose(Hamlin et al., 2006), alcohol (Hamlin et al., 2007), and cocaine(Cruz et al., 2014) seeking. Antagonism of dopamine D1-likereceptors in accumbens shell attenuates context-inducedreinstatement of both alcohol and heroin seeking (Bossertet al., 2007; Chaudhri et al., 2009). Antagonism of glutamatereceptors in accumbens shell blocks context-induced rein-statement of cocaine seeking (Fuchs et al., 2008; Xie et al.,2012) and suppression of glutamate transmission throughactivation of mGluR2/3 receptors attenuates context-inducedreinstatement of heroin seeking (Bossert et al., 2006a). Finally,selective inactivation of the reinstatement-associated Fosneurons in accumbens shell, using the Daun02 inactivationprocedure (Koya et al., 2009), attenuates context-inducedreinstatement of cocaine seeking (Cruz et al., 2014).

One possible reason that accumbens shell is critical forreinstatement induced by drug-context associations isbecause it receives strong projections from ventral hippo-campus, which has been demonstrated to be critical forcontext-induced reinstatement of both heroin and cocaineseeking (Bossert and Stern, 2014; Lasseter et al., 2010). Inter-estingly, using optogenetics to measure the synaptic strengthof different projections to accumbens shell, Britt et al. (2012)found that synaptic currents induced by optical stimulationof ventral hippocampus projections to accumbens shell arestronger than BLA or mPFC projections. As such, it is possiblethat the conserved role of accumbens shell in mediatingcontext-induced reinstatement across multiple drug types isdriven in part by strong inputs from ventral hippocampus,which are presumably conveying the motivational signifi-cance of the drug-associated contexts.

One of the main differences that have emerged in theliterature reviewed above is that context-induced reinstate-ment of different classes of drugs is mediated by differentsub-regions of mPFC and the corresponding projections tonucleus accumbens. Reversible inactivation of dorsal, but notventral, mPFC decreases context-induced reinstatement ofalcohol or cocaine seeking (Fuchs et al., 2005; Willcocks andMcNally, 2012). In contrast, reversible inactivation of ventral,but not dorsal, mPFC attenuates context-induced reinstate-ment of heroin seeking (Bossert et al., 2011). Additionally,Peters et al. (2008) have shown that extinguished cocaineseeking is reinstated by reversible inactivation of ventral butnot dorsal mPFC. This effect was shown to be dependent onaccumbens shell, because reinstatement induced by unilat-eral inactivation of ventral mPFC was increased when theipsliateral or contralateral accumbens shell was also


inactivated. In contrast, this inhibitory role of the ventralmPFC to accumbens shell projection is not seen in ratstrained to self-administer heroin. Bossert et al. (2012) haveshown that disconnection of ventral mPFC





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(muscimolþbaclofen) and accumbens shell (D1-like receptorantagonist) decreases context-induced reinstatement of her-oin seeking; this manipulation has no effect on extinctionresponding. Taken together, these findings demonstrate thatthere are significant differences in the corticostriatalcontrol over context-induced cocaine, heroin, and alcoholseeking.

An important consideration towards understanding theconflicting data on mPFC projections to nucleus accumbens isthe overlapping projections of ventral and dorsal mPFC to thenucleus accumbens. An influential review article from Peterset al. (2009) proposed behaviorally opposite roles for dorsal andventral mPFC projections to accumbens core and shell, respec-tively. They proposed that dorsal mPFC to accumbens coreprojections promote drug seeking while ventral mPFC toaccumbens shell projections inhibit drug seeking. While thereis some evidence for this dichotomy in the case of cocaineseeking (Peters et al., 2008), a close examination of the originalanatomical studies describing the mPFC projections to nucleusaccumbens shows that the anatomical evidence does notsupport this kind of parallel circuitry. Both retrograde (Broget al., 1993) and anterograde (Sesack et al., 1989) tracing studiesshow that accumbens core receives dense projections fromboth ventral and dorsal mPFC. As such, a potentially importantconsideration that is overlooked is the extent to which ventralmPFC projections to accumbens core contributes to the promo-tion or inhibition (as in extinction) of drug seeking (Fig. 1).

4. Conclusions and future directions

The data reviewed above show there are significant simila-rities (accumbens shell, ventral hippocampus, BLA) anddifferences (mPFC and its projections to accumbens) in theneural mechanisms of context-induced reinstatement ofheroin, cocaine, and alcohol seeking. The extent to whichthe different experimental parameters used in differentlaboratories (Box 1) accounts for these results is not known(Crombag et al., 2008). Unfortunately, there are no studiesspecifically examining these differences in a single experi-ment with different groups of rats trained to self-administerheroin, cocaine, or alcohol. Procedural differences aside, asdiscussed previously (Badiani et al., 2011), we propose thatone potential contributing factor for these differences is thedifferent motivational states induced by these drugs. There isa large body of evidence showing that different drug-inducedmotivational states are mediated by different neural sub-strates (Badiani et al., 2011; Badiani, 2013; Caprioli et al., 2007;Ettenberg, 2004, 2009). As such, we speculate that differentdrug-associated contexts induce drug seeking through differ-ent mechanisms because of the unique motivational stateeach drug induces.

Finally, we have recently developed an alternative renewalprocedure to study context-induced relapse to alcohol seek-ing after suppression of alcohol taking by adverse conse-quences (Marchant et al., 2013a). We developed thisprocedure because, as has been noted in the literature,extinction does not adequately capture the motivation forabstinence in humans (Epstein et al., 2006; Katz and Higgins,


2003; Marlatt, 2002; Tiffany and Conklin, 2002). Rather, inhumans abstinence is typically self-imposed despite drugavailability, often out of a desire to avoid the negativeconsequences associated with excessive drug use (Burman,1997; Klingemann, 1991).

To model this phenomenon, we used response-contingentpunishment, with electric foot-shock, in place of extinction tosuppress alcohol taking in context B. Importantly, we foundthat the footshock must be contingent on alcohol-reinforcedlever pressing to suppress alcohol taking. Rats that receivednon-contingent foot-shock during context B self-administrationdo not suppress alcohol intake, or alcohol seeking on test ineither context A or B. After punishment-imposed abstinence incontext B, the observed behavior on test is similar to that seenin context-induced reinstatement after extinction (Marchantet al., 2013a). We found suppressed alcohol seeking in context B,in the absence of foot-shock, and renewed alcohol seeking ontest in context A. Given the similarities in the behavioral profileof the two procedures, our main research question is whetherthe neural mechanisms of context-induced reinstatement afterpunishment versus after extinction are different (Marchantet al., 2013b). In short, does it matter if drug seeking issuppressed by extinction or adverse consequences?

We recently published our first attempt at characterizingthe neural mechanisms of context-induced relapse to alcoholseeking after punishment-imposed abstinence (Marchantet al., 2014). We found that this relapse is associated withincreased Fos expression in lateral hypothalamus (LH) neu-rons, and that LH neuronal activity is necessary becausereversible inactivation (muscimolþbaclofen) decreasedcontext-induced relapse. Both increased LH Fos expression,and a necessary role for LH neuronal activation have pre-viously been shown for context-induced reinstatement afterextinction (Hamlin et al., 2007; Marchant et al., 2009). As such,at least for the role of LH in context-induced alcohol seeking,the procedure used to suppress alcohol seeking (extinction orpunishment) does not change the subsequent neuralmechanisms of context-induced drug seeking. In addition,context-induced alcohol seeking after either extinction orpunishment is associated with increased Fos expression inaccumbens shell neurons that project to LH (Marchant et al.,2009, 2014). This suggests that LH is a critical output target ofaccumbens shell that is associated with context-inducedalcohol seeking, regardless of the mechanism used to sup-press alcohol seeking. In the context of our review, animportant question for future research is whether the corti-costriatal circuits described above mediate context-inducedrelapse to drug seeking after punishment-imposedabstinence.

Acknowledgments

Research was supported by the National Institute on DrugAbuse, Intramural Research Program. N.J.M. received supportfrom Early Career Fellowship 1053308 by the National Healthand Medical Research Council. The authors declare that theydo not have any conflicts of interest (financial or otherwise)related to the data presented in this manuscript.





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Role of corticostriatal circuits in context-induced reinstatement of drug seeking