Prefrontal cortex plasticity mechanisms in drug seeking and relapse

Neuroscience and Biobehavioral Reviews 35 (2010) 276–284

Review

Prefrontal cortex plasticity mechanisms in drug seeking and relapse

Michel C. Van den Oever a,*, Sabine Spijker a, August B. Smit a, Taco J. De Vries a,b

a Dept. Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085,

1081 HV Amsterdam, The Netherlandsb Dept. Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU Medical Center, The Netherlands

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

2. Drug craving is associated with altered PFC activity in addicts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

3. Preclinical evidence for a role of the mPFC in drug seeking and relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

4. Neurocircuitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

4.1. Corticostriatal projections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

4.2. Ventral tegmental area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

4.3. Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

5. Long-term drug-induced neuroadaptations in the mPFC-NA pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

6. Acute synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

7. Clinical implications and future perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

A R T I C L E I N F O

Keywords:

Addiction

Relapse

Prefrontal cortex

Cocaine

Heroin

Reinstatement

Neuroadaptations

A B S T R A C T

Development of pharmacotherapy to reduce relapse rates is one of the biggest challenges in drug

addiction research. The enduring nature of relapse suggests that it is maintained by long-lasting

molecular and cellular adaptations in the neuronal circuitry that mediates learning and processing of

motivationally relevant stimuli. Studies employing the reinstatement model of drug relapse in rodents

point to an important role of the medial prefrontal cortex (mPFC), with distinct contributions of the

dorsal and ventral regions of the mPFC to drug-, stress- and cue-induced drug seeking. Whereas drug-

induced neuroadaptations in the dorsal mPFC function to enhance excitatory output and drive

expression of drug seeking, recent evidence suggests that plasticity in the ventral mPFC leads to reduced

glutamatergic transmission in this region, thereby impairing response inhibition upon exposure to drug-

conditioned stimuli. Treatments aimed at restoring drug-induced neuroadaptations in the mPFC may

help to reduce cue-reactivity and relapse susceptibility.

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1. Introduction

Drug addiction is characterized by compulsive drug-takingbehavior and high rates of relapse even after many years ofabstinence. From a clinical perspective, the enduring vulnerabilityto relapse is an obvious entry point for effective pharmacother-apeutic intervention (Kalivas and Volkow, 2005; O’Brien, 2003).

* Corresponding author. Tel.: +31 20 5987111; fax: +31 20 5989281.

E-mail address: [email protected] (M.C. Van den Oever).

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However, most available treatments are still relatively ineffective,because little information is available on the molecular and cellularunderpinnings of relapse. In order to develop pharmaceuticals thatreduce relapse susceptibility, it is of crucial importance to gaininsight into the neuronal mechanisms underlying the developmentof a drug addictive state as well as the acute plasticity mechanismsthat trigger relapse.

Generally, it is thought that repeated drug intake leads topersistent neuroadaptations that strengthen the desire to obtainthe drug and the processing of drug-conditioned stimuli (O’Brienet al., 1986; Robinson and Berridge, 1993; Shaham and Hope,

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M.C. Van den Oever et al. / Neuroscience and Biobehavioral Reviews 35 (2010) 276–284 277

2005; Thomas et al., 2008). The predominant focus in addictionresearch has initially been on the role of the mesolimbic dopaminesystem. The action that most drugs of abuse have in common is tostimulate dopaminergic transmission, either by directly increasingthe firing of dopaminergic neurons in the ventral tegmental area(VTA) or by enhancing extracellular dopamine levels in the nucleusaccumbens (NA) (Di Chiara and Imperato, 1988; Hyman et al.,2006). This suggests that the mesolimbic dopamine system is alikely substrate for drug-induced neuroadaptations that mediateaddiction related behaviors. Indeed, several neuroadaptationshave been identified in the NA that provided insight in the effectsof acute drug administration and the development of addictivebehaviors associated with chronic drug exposure, such as toleranceand dependence (Nestler, 2001; Nestler et al., 2001). For instance,increased expression of cAMP response element binding protein(CREB) in the NA after repeated drug exposure is thought tomediate tolerance and a state of dysphoria during early with-drawal (Barrot et al., 2002; Carlezon et al., 1998). However, the factthat relapse susceptibility persists long after the positive andnegative reinforcing effects of the drug have subsided suggests thatthere might be additional neuronal substrates undergoing long-lasting neuroadaptative changes. During the last decade, cognitiveprocesses that accompany drug self-administration (SA) receivedmore attention, which led to the concept that addiction is alearning and memory disorder that involves mechanisms ofneuroplasticity similar to traditional models of learning andmemory (Everitt and Wolf, 2002; Hyman, 2005; Jones and Bonci,2005; Kauer and Malenka, 2007). This view shifted focus to the roleof the neocortex and corticofugal glutamate projections in theacquisition of drug SA and the long-lasting propensity to relapse(Kalivas, 2004; Robbins et al., 2008).

Substantial evidence points to the involvement of the mPFC inreinforcement learning and acquisition of drug SA (Tzschentke,2000). Acquisition of drug SA is associated with altered neuronalactivity in the mPFC, as measured by an increase in the expressionof Arc (Fumagalli et al., 2009). More specifically, firing of mPFCneurons can be closely time-locked to i.v. injections of cocaine andheroin (Chang et al., 1998) and changes in dopamine levels havebeen reported in response to food reward (Richardson and Gratton,1998). In support of a role of dopaminergic transmission, 6-hydroxydopamine lesions of the mPFC enhance cocaine SA byincreasing sensitivity to the reinforcing effects of cocaine (Schenket al., 1991). Moreover, excitotoxic lesions of the mPFC facilitateacquisition of cocaine SA (Weissenborn et al., 1997), which maypoint to a loss of behavioral inhibition after disruption of mPFCfunction. Taken together, these studies suggest that the mPFCmight be a neuronal substrate for drug-induced neuroadaptationsthat maintain relapse susceptibility. In support of this, human andanimal studies indicate that the mPFC functions as a final relaystation in relapse evoked by drugs, stress and drug-conditionedstimuli (Kalivas et al., 2005; Kalivas and Volkow, 2005). Here, wewill review the role of the mPFC in relapse to drug seeking in lightof novel exciting insights from studies that utilized the rodent drugreinstatement model. Despite recent advances in the under-standing of the role of the mPFC in relapse, relatively little is knownof the molecular and cellular adaptations that result in alteredfunctioning of mPFC neurons and those maintaining persistentsusceptibility to relapse.

2. Drug craving is associated with altered PFC activity in addicts

It is well established that the PFC is involved in mediating theprimary rewarding effects of reinforcing stimuli, including drugs ofabuse (Tzschentke, 2000). In addition, human imaging studies haveimplicated the PFC in feelings of craving and drug seeking elicitedby drug-conditioned stimuli during periods of drug abstinence. For

instance, a persistent reduction is observed in PFC measures ofcellular metabolism and blood flow in psychostimulant and opioidabusers (Botelho et al., 2006; Goldstein and Volkow, 2002). Incontrast, increased metabolic activity or blood flow in dorsal PFCareas is observed when addicts are exposed to drug-associatedstimuli (Childress et al., 1999; Goldstein and Volkow, 2002; Grantet al., 1996; Langleben et al., 2008), reflecting neuronal activity inthese areas during cue-evoked drug craving. Notably, decreasedactivity has been reported in the ventral mPFC upon exposure tococaine-related cues (Bonson et al., 2002). These studies suggestthat drug craving elicited by drug-associated stimuli is accom-panied by hyperfunction and hypofunction of the dorsal andventral mPFC, respectively. In addition, addicts are characterizedby a reduced incentive for obtaining naturally rewardingsubstances (Goldstein and Volkow, 2002) and they exhibitdecreased cingulate cortex activation in response to naturallyrewarding stimuli (Garavan et al., 2000). Taken together, theseprocesses are thought to contribute to: (1) a reduced capacity ofthe PFC to initiate behaviors in response to natural rewards, (2) anincreased responsivity to drug-conditioned cues and (3) a reducedinhibitory control over drug seeking (Bechara, 2005; Kalivas andVolkow, 2005). Hence, human studies emphasize the importanceof studying the maladaptive functioning of mPFC neurons afterdrug exposure at the cellular and molecular level.

3. Preclinical evidence for a role of the mPFC in drug seekingand relapse

Relapse to drug seeking can be modeled successfully in animals.In particular, operant responding for drugs of abuse can beextinguished and subsequently reinstated by acute exposure to thedrug itself, stress or conditioned stimuli that were paired with thedrug during self-administration (De Vries et al., 2001; Epstein et al.,2006; Shalev et al., 2002). In this model, reinstatement of cocaine-and heroin seeking by all three stimulus modalities can be blockedby reversible pharmacological inactivation of the dorsal mPFC(anterior cingulate and dorsal prelimbic area; Fig. 1) (Fuchs et al.,2005; McFarland and Kalivas, 2001; McLaughlin and See, 2003;Rogers et al., 2008). In line with these findings, we and others havefound that reinstatement is accompanied by increased neuronalactivation in the dorsal mPFC, as measured by the enhancedexpression of immediate early genes (IEGs) (Ciccocioppo et al.,2001; Koya et al., 2006; Schmidt et al., 2005; Zavala et al., 2008).Moreover, a differential pattern of neuronal activation was foundin the mPFC upon cue-induced heroin seeking versus sucrose (anon-drug reinforcer) seeking (Koya et al., 2006; Schmidt et al.,2005), suggesting that distinct neuronal mechanisms in the mPFCregulate the expression of drug seeking and natural reward-seeking by conditioned stimuli. Although the dorsal mPFC iscritically involved in reinstatement of drug seeking followingextinction learning, pharmacological inactivation of the dorsalmPFC after a period of abstinence in the animal’s home-cage has noeffect on cocaine seeking induced by cocaine cues (Fuchs et al.,2006; Koya et al., 2009). This suggests that the neuronal substratescontrolling reinstatement after extinction are different from thosemediating relapse after forced abstinence and that the dorsal mPFCis recruited during extinction training. However, similar to cocaineseeking after extinction, increased neuronal activity was observedin the dorsal mPFC when a relapse test was performed followingabstinence (Hearing et al., 2008; Koya et al., 2009; Zavala et al.,2007). This argues for the manipulation of specific signaltransduction pathways to investigate the role of the dorsal mPFCin drug seeking after abstinence more thoroughly. Also, it remainsto be determined whether the lack of effect of dorsal mPFCinactivation on conditioned cocaine seeking after abstinencegeneralizes to other drugs of abuse, such as heroin.

Fig. 1. The mPFC functions as a final relay station in relapse to drug seeking. Left: coronal section of the rodent prefrontal cortex. Subregions of the mPFC are depicted in

different colors. Based on functional and anatomical characteristics, the mPFC can be divided into a dorsal region encompassing the anterior cingulate (AC) and dorsal

prelimbic area (PLd) and a ventral region that includes the ventral prelimbic area (PLv) and infralimbic area (IL). Right: The mPFC mediates reinstatement induced by drugs,

stress and drug-conditioned stimuli. Dopaminergic projections from the VTA to the dorsal mPFC (dmPFC) drive drug seeking responses. Moreover, glutamatergic projections

originating in the BLA may promote drug seeking induced by conditioned cues. In turn, the limbic circuit engages the motor circuitry through a glutamatergic projection from

the dmPFC to the NA core (NAc), thereby initiating drug seeking responses. The ventral mPFC (vmPFC) can suppress reinstatement through a glutamatergic projection to the

NA shell (NAs), a function that may be impaired after re-exposure to drugs or drug-associated stimuli.

M.C. Van den Oever et al. / Neuroscience and Biobehavioral Reviews 35 (2010) 276–284278

In contrast to the attenuating effect of dorsal mPFC inactivationon reinstatement, reversible inactivation of the ventral mPFC(ventral prelimbic and infralimbic area; Fig. 1) results inresumption of cocaine seeking under extinction conditions (Peterset al., 2008). Moreover, stimulation of glutamatergic transmissionin this area attenuates cocaine-primed reinstatement (Peters et al.,2008). Context-induced reinstatement of cocaine seeking isassociated with increased Fos expression in the ventral mPFC(Hamlin et al., 2008), suggesting that enhanced, as opposed toreduced, neuronal activity mediates expression of this behavior.However, it is not known which neuronal subtypes exhibitincreased activity during context-induced cocaine seeking.Enhanced Fos expression may have occurred predominantly ininhibitory interneurons, which would reflect a dampening of theactivity of excitatory neurons (Markram et al., 2004). Alterna-tively, increased Fos expression in the ventral mPFC may reflectextinction learning upon non-reinforced exposure to the cocaine-conditioned context. The ventral mPFC is thought to exertinhibitory control over cocaine seeking after extinction ofresponding has occurred (Peters et al., 2008), similar to itsfunction in extinction of conditioned fear (Milad and Quirk, 2002;Peters et al., 2009). In contrast, ventral mPFC inactivation afterlong-term abstinence attenuates conditioned cocaine seeking(Koya et al., 2009). It is not known whether this differential roleof the ventral mPFC in cocaine seeking after extinction andabstinence generalizes to other drugs of abuse. Studies on cue-induced heroin seeking after extinction have reported inconsistenteffects of pharmacological inactivation of the ventral mPFC.Schmidt et al. (2005) showed that inactivation of the ventralprelimbic area potentiated cue-induced heroin seeking, however,Rogers et al. (2008) reported that ventral mPFC inactivationattenuated cue-induced and heroin-primed reinstatement. Thediscrepancy of these results may be explained by the duration ofthe reinstatement sessions (15 min in Schmidt et al. versus 3 h byRogers et al.), which could reflect a differential role of the ventralmPFC in initiation versus maintenance of heroin seeking byconditioned cues. Moreover, extinction processes are more likelyto occur during prolonged exposure to conditioned cues introdu-cing the possibility that parallel circuits are recruited as well asadditional compensatory changes (Mamiya et al., 2009; Suzuki etal., 2004). In line with the observations by Schmidt et al.,inactivation of the ventral mPFC enhanced heroin seeking afterextinction in a conditioned place preference paradigm (Ovari andLeri, 2008). Furthermore, the potentiating effect of ventralprelimbic inactivation on conditioned heroin seeking is supported

by our recent observation that blockade of AMPA receptor (AMPA-R) endocytosis (which maintained glutamatergic synapticstrength) in the ventral mPFC attenuated cue-induced reinstate-ment of heroin seeking (Van den Oever et al., 2008). This suggeststhat glutamatergic transmission in the ventral mPFC acts tosuppress responding to drug-associated cues (discussed below).

4. Neurocircuitry

4.1. Corticostriatal projections

Altered functioning of the mPFC during relapse events reflectsmaladaptive responding of neurons to information that enters themPFC and the propagation of information to other brain regions.Studies by Kalivas et al. (2005) strongly support a change in mPFCglutamatergic output to the NA during reinstatement of drugseeking. Anatomically, projections from the mPFC to the NA areorganized in a dorsal–ventral pattern, with the dorsal mPFCprojecting predominantly to the NA core and the ventral mPFC tothe NA shell (Fig. 1) (Heidbreder and Groenewegen, 2003; Voorn etal., 2004). Reinstatement is accompanied by an increase ofextracellular glutamate in the NA core that is thought to drivedrug seeking (Cornish et al., 1999; LaLumiere and Kalivas, 2008;McFarland et al., 2004, 2003). In support of this, inhibition ofglutamatergic transmission in the NA core blocks responding toreinstating stimuli (Cornish and Kalivas, 2000; LaLumiere andKalivas, 2008; Ping et al., 2008) and long-term cocaine abstinenceis associated with increased AMPA-R expression in the NA core andshell (Conrad et al., 2008). The rise in NA core glutamate can beevoked by injection of cocaine directly into the mPFC (Park et al.,2002) and can be prevented by pharmacological inactivation ofdorsal mPFC projections to the NA core (LaLumiere and Kalivas,2008; McFarland et al., 2004, 2003). Together, these studiesindicate that following extinction of drug self-administration,excitatory neurons in the dorsal mPFC projecting to the NA core arehighly responsive to reinstating stimuli.

Glutamatergic projections from the ventral mPFC to the NA shellare thought to suppress conditioned drug seeking after extinctionlearning (Fig. 1) (Peters et al., 2009), as disconnection of thispathway results in resumption of cocaine seeking (Peters et al.,2008) and pharmacological inactivation of the NA shell increasescocaine seeking under extinction conditions (Fuchs et al., 2008;Peters et al., 2008). This is in line with the observation thatextinction of cocaine seeking is paralleled by increased expression ofAMPA-Rs in the NA shell and that cue-induced reinstatement is

Fig. 2. Potential molecular mechanisms by which drug-induced adaptations alter neuronal activity in the mPFC during abstinence/extinction and relapse. Schematic

representation of a neuron in the dorsal and ventral mPFC. Prolonged abstinence from repeated drug exposure is associated with increased expression of AGS3, NMDA-Rs and

L-type Ca2+ channels. Upregulation of AGS3 in the dorsal mPFC is thought to limit signaling through D2 receptors (D2-R), resulting in a relative increase in D1 receptor (D1-R)

signaling. This, combined with an increase in the abundance of L-type Ca2+ channels may enhance responsivity of dorsal mPFC neurons to drug-associated stimuli, thereby

maintaining relapse vulnerability. The contribution of enhanced NMDA-R expression to neuronal physiology is unknown and may normalize upon cue-exposure. In the

ventral mPFC, activation of AMPA-Rs, and possibly L-type Ca2+ channels, suppresses conditioned drug seeking after extinction. Upon exposure to drug-associated cues, the

activity of ventral mPFC pyramidal neurons may be impaired by acute endocytosis of AMPA-Rs. The role of dopaminergic transmission in the ventral mPFC after drug

exposure and during relapse remains to be elucidated.


negatively correlated with GluA1 (GluR1) expression in that area(Sutton et al., 2003). Moreover, reversible inactivation of the NAshell and blockade of NMDA receptors (NMDA-Rs) facilitatesreinstatement of cocaine seeking (Di Ciano et al., 2007; Famouset al., 2007). However, a substantial number of studies contradictthis theory by showing that pharmacological inactivation of the NAshell attenuates drug-, cue- and stress-induced reinstatement ofdrug seeking behavior (Fuchs et al., 2008; McFarland et al., 2004;Rogers et al., 2008). A similar effect on drug seeking has beenobserved for glutamate receptor and dopamine receptor blockade inthe NA shell (Anderson et al., 2003, 2006; Bachtell et al., 2005;Bossert et al., 2006, 2007; Famous et al., 2008; Fuchs et al., 2008;McFarland et al., 2004; Rogers et al., 2008; Schmidt and Pierce, 2006;Xi et al., 2004). The discrepancy in these findings might be explainedby the absence or presence of non-extinguished reinstating stimuliduring tests for drug seeking behavior. Reduced NA shell functionmay attenuate responding when non-extinguished stimuli areintroduced during testing, but may facilitate responding duringmere extinction conditions. This supports the need for a thoroughanalysis of neuronal subtypes and signal transduction pathways thatcontrol drug seeking. For instance, distinct neuronal ensembleswithin the NA shell may regulate different behavioral components(e.g. initiation and extinction; see also, Pennartz et al., 1994) ofconditioned drug seeking.

4.2. Ventral tegmental area

Apart from the NA, the mPFC is heavily interconnected withseveral other brain regions that are critically involved inreinstatement of drug seeking, such as the VTA (Heidbreder andGroenewegen, 2003; McDonald, 1987; Sesack et al., 1989; Thierryet al., 1973). Dopaminergic neurons in the VTA project to the mPFCvia the corticolimbic dopamine pathway that is thought to processreward salience and the predictive value of reward-paired stimuli(Schultz, 1998; Tzschentke, 2001). Dopaminergic projections tothe dorsal mPFC are involved in the initiation of drug seeking

responses, as it was found that dopamine is released in the dorsalmPFC during reinstatement, and intra-mPFC injection of dopaminereceptor agonists trigger drug seeking, whereas dopamine receptorantagonists attenuate this behavior (Capriles et al., 2003; McFar-land and Kalivas, 2001; Park et al., 2002; See, 2009; Sun and Rebec,2005). Moreover, systemic blockade of D1 receptors prevents anincrease in Fos expression in the dorsal mPFC (Ciccocioppo et al.,2001), suggesting that dopaminergic transmission increasesneuronal activity in this area during reinstatement. Althoughthe ventral mPFC also receives dense dopaminergic innervation(Heidbreder and Groenewegen, 2003), the role of ventral mPFCdopaminergic transmission in conditioned drug seeking has notbeen thoroughly investigated yet.

4.3. Amygdala

The basolateral nucleus of the amygdala (BLA) has densereciprocal glutamatergic connections with the mPFC (McDonald,1987; Sesack et al., 1989) and is a key neuronal substrate thatcontrols cue-induced reinstatement of drug seeking (Crombaget al., 2008; See et al., 2003). Pharmacological inactivation of theBLA blocks cue-induced cocaine and heroin seeking (Fuchs and See,2002; McLaughlin and See, 2003). Moreover, pharmacologicaldisconnection of the BLA and dorsal mPFC attenuates context-induced cocaine seeking (Fuchs et al., 2007), suggesting thatfunctional interaction between these two structures drivesconditioned drug seeking responses (Fig. 1). The amygdala is alsocritically involved in the expression of conditioned fear memory(Han et al., 2009; Schafe et al., 2005) and it is well established thatthe ventral mPFC mediates extinction of fear memory (Santini etal., 2008) by dampening the output from central amygdala neuronsthrough excitation of intercalated inhibitory cells (ITCs) in theamygdala (Quirk et al., 2003). Therefore, ventral mPFC projectionsto the amygdala may have a similar function in extinction ofconditioned drug seeking, although evidence is lacking. DopamineD1 receptor activation, but not D2 receptor nor glutamate receptor


activation, in the BLA is required for cue-induced reinstatement ofcocaine seeking (See et al., 2001). The activity of ITCs in the BLA isinhibited by dopamine via D1 receptors, which is thought result inan overall disinhibition of the amygdala (Marowsky et al., 2005).Potentially, dopamine release in the BLA may promote cue-eliciteddrug seeking by blocking ventral mPFC mediated excitation of ITCsin the BLA.

To summarize, the mPFC is thought to function as a relay stationin stimulus-induced drug seeking, as multiple inputs to the dorsalmPFC may drive relapse behavior. Conditioned drug seeking isaccompanied by an increase in dopamine release in the mPFC andactivation of dopamine D1 receptors is required for reinstatement(Fig. 2). This suggests that upon exposure to strong motivationalstimuli, dopaminergic input to the dorsal mPFC during relapse mayserve to increase the excitability of glutamatergic pyramidalneurons in the dorsal mPFC. Furthermore, interactions of the BLAwith the dorsal mPFC promote drug seeking by processing themotivational salience of drug-associated cues (Fuchs et al., 2007).In turn, a glutamatergic projection from the dorsal mPFC to the NAcore is thought to engage the motor circuitry, thereby driving drugseeking responses. Less is known about functional interactions ofthe ventral mPFC with its input and output structures. Recentobservations indicate that ventral mPFC glutamatergic output tothe NA shell functions to suppress drug seeking after extinctionlearning (Fig. 1) (Peters et al., 2008). However, the NA shell has alsobeen heavily implicated in reinstatement of drug seeking,suggesting that input from other brain structures (e.g. VTA, BLA)than the ventral mPFC may drive drug seeking responses.Alternatively, ventral mPFC interactions with the amygdala mayalso play an important role in conditioned drug seeking,considering the fact that these brain regions are heavilyinterconnected and given the role of this interaction in extinctionof conditioned fear. Importantly, it remains to be determinedwhether functional interaction of the mPFC with its efferenttargets is different after abstinence versus extinction learning.

5. Long-term drug-induced neuroadaptations in the mPFC-NApathway

The enduring nature of relapse to drug seeking and thepersistent involvement of the mPFC suggest that relapse suscept-ibility is maintained by long-lived neuroadaptations that alter theresponsivity of mPFC neurons to relapse-eliciting stimuli. Unfor-tunately, persistent drug-induced molecular and cellular changesin the mPFC have not been as well characterized as in the NA, andthe majority of studies examined neuroadaptations resulting fromcocaine administration only. Moreover, it is not always knownwhether identified neuroadaptations are the result of repeatedcontingent drug exposure or whether they overlap with alterationsresulting from more general reward learning processes. This is ofrelevance, as we found that self-administration of a natural reward(sucrose) leads to long-term molecular changes in the mPFC (Vanden Oever et al., 2006). In addition, active (response contingent)drug administration produces pronounced differences in geneexpression patterns in the NA when compared to passive drugadministration (Jacobs et al., 2003, 2002). Nevertheless, cocaine-induced adaptations provided valuable insight in the alteredfunctioning of dorsal mPFC neurons after drug exposure and therole of prefrontal glutamatergic projections to the NA duringrelapse. For instance, several drug-induced neuroadaptations havebeen identified that alter the excitability of medium spiny neuronsto glutamatergic input from the mPFC (for excellent reviews seeKalivas, 2009; Thomas et al., 2008). In general, it is thought thatglutamatergic transmission at mPFC-NA core synapses is aug-mented due to reduced basal extracellular glutamate levels (Bakeret al., 2003), increased surface expression of glutamate receptors

(Boudreau et al., 2007; Conrad et al., 2008), and altered expressionof post-synaptic density proteins (Szumlinski et al., 2004; Yao etal., 2004) in the NA core during drug abstinence. Moreover, a recentstudy by Kourrich and Thomas showed that cocaine exposureresults in increased intrinsic firing capacity of NA core neurons,whereas NA shell neurons exhibit reduced firing capacity (Kourrichand Thomas, 2009), providing a parallel counterpart to the distinctroles of the dorsal and ventral mPFC and their projection patternswithin the NA in conditioned drug seeking.

Despite the identification of drug-induced adaptations inglutamatergic transmission within the NA, relatively few gluta-matergic adaptations have been reported for the mPFC. Moreover,little information exists on the anatomical localization of identifiedneuroadaptations in the mPFC, as most molecular analyses did notdistinguish between the dorsal and ventral mPFC. Long-termcocaine abstinence is accompanied by increased expression ofNMDA-R subunits in the dorsal mPFC (Fig. 2) (Ben-Shahar et al.,2009; Tang et al., 2004). In support of a role of NMDA-Rs in relapse,we recently found that cue-induced heroin seeking is associatedwith a rapid down-regulation in the synaptic membrane expres-sion of the GluN2B subunit (NR2B), however, changes in NMDA-Rplasticity in mPFC pyramidal neurons were not observed (Van denOever et al., 2008). Hence, at present it is not known how andwhether drug-induced changes in NMDA-R expression affect drugseeking and glutamatergic plasticity in the mPFC. Studies byRobinson and Kolb provide evidence that drug self-administrationresults in persistent changes in neuronal morphology and synapticrearrangements of excitatory neurons in the mPFC. Whereaspsychostimulants increase neuronal branching and spine densityof prelimbic pyramidal neurons (Crombag et al., 2005; Robinson etal., 2001), opiate exposure reduces pyramidal neuron complexity(Robinson et al., 2002). Although these observations may indicatethat cellular adaptations are drug-specific, the functional con-tribution of neuronal morphology changes in the mPFC to relapsevulnerability remains to be determined. The increase in spinedensity during cocaine abstinence may indicate that glutamatergicinput to pyramidal neurons in the prelimbic area is altered,possibly favoring input from afferent regions that drive relapsebehavior. Furthermore, the excitability of mPFC pyramidal neuronsmay be altered by a persistent increase in surface expression of L-type Ca2+ channels after cocaine exposure (Fig. 2) (Ford et al.,2009), which may potentially enhance the responsivity of thesecells to drug-associated stimuli. This is supported by theobservation that Ca2+ influx in mPFC pyramidal neurons isenhanced after membrane depolarization during cocaine absti-nence (Nasif et al., 2005). As the latter studies did not distinguishbetween the dorsal and ventral mPFC, it is not known whether thechange in L-type Ca2+ channels expression occurs in the dorsal orventral mPFC. Increased L-type Ca2+ channel expression in thedorsal mPFC may potentially enhance drug seeking by increasingthe responsivity of dorsal mPFC pyramidal neurons to drug-associated stimuli. Alternatively, L-type calcium channel activa-tion in the ventral mPFC during abstinence may facilitateextinction learning, considering the role of these calcium channelsin extinction of conditioned fear (Busquet et al., 2008; Suzuki et al.,2004).

Abstinence from chronic cocaine treatment is associated withincreased expression of activator of G-protein signaling 3 (AGS3) inthe mPFC (Bowers et al., 2004), a protein that limits signaling ofGia-coupled receptors. Upregulation of AGS3 is thought to resultin a reduction of D2 relative to D1 receptor signaling (Fig. 2)(Kalivas et al., 2005; Nogueira et al., 2006). This finding is in linewith reduced D2 receptor binding in human addicts duringabstinence (Goldstein and Volkow, 2002), and with the critical roleof D1, but not D2, receptor activation in reinstatement of drugseeking (Capriles et al., 2003; See, 2009; Sun and Rebec, 2005). A


relative increase in mPFC ‘D1 tone’ is thought to reduce behavioralflexibility and result in a state in which only strong stimuli (e.g.drugs or conditioned cues) are capable of guiding behavior(Seamans and Yang, 2004). Normalization of AGS3 expression,which may restore ‘D2 tone’, in the prelimbic area after cocaineself-administration prevents reinstatement of cocaine seeking(Bowers et al., 2004). Recently, it was found that a single injectionof brain derived neurotrophic factor (BDNF) into the dorsal mPFCduring early abstinence is sufficient to attenuate cocaine-primedreinstatement (Berglind et al., 2007) and to prevent thereinstatement associated increase in glutamate release in theNA core (Berglind et al., 2009). This suggests that intra-mPFC BDNFtreatment immediately after drug cessation may counteract thesubsequent development of drug-induced neuroadaptations thatalter mPFC glutamatergic output to the NA core. However, theexact cellular and molecular mechanisms that are affected byBDNF treatment after cocaine SA are currently unknown.

6. Acute synaptic plasticity

Apart from long-lasting drug-induced neuroadaptations,relapse is thought to be initiated by acute drug-, stress- or cue-induced changes in synaptic plasticity. In particular, acute changesin glutamatergic transmission in the NA, VTA and amygdala havebeen implicated in expression of psychomotor sensitization andrelapse to drug seeking (Brebner et al., 2005; Jones and Bonci,2005; Kourrich et al., 2007; Lu et al., 2005), but very little is knownabout acute mechanisms of synaptic plasticity in the mPFC. Therecent development of highly sensitive proteomics technologyenables the analysis of drug-induced molecular changes at thesynaptic level. A major advantage of probing protein changes at thesynapse, as opposed to the whole cell, is that synaptic adaptationsare more likely to correlate with changes in neuronal physiology.Moreover, identification of synaptic adaptations has high potentialto yield targetable substrates for (novel) compounds that canprevent relapse to drug seeking.

Recently, we successfully implemented a quantitative proteo-mics approach to show that cue-induced heroin seeking isassociated with a rapid (within 1 h) decrease in synapticmembrane expression of AMPA-R subunits GluA2 (GluR2) andGluA3 (GluR3) and a concomitant increase in the clathrin-coatassembly protein AP-2 complex subunit mu-1 (Van den Oever etal., 2008), pointing to acute endocytosis of synaptic AMPAreceptors upon exposure to heroin-associated cues. In agreementwith this, a decrease in glutamatergic synaptic strength (expressedas a change in AMPA/NMDA current ratio) and rectification ofAMPA currents was observed at glutamatergic synapses ofpyramidal neurons after a relapse test. Furthermore, inhibitionof clathrin-dependent GluA2 endocytosis with the syntheticpeptide TAT-GluR23Y administered either systemically or locallyin the ventral mPFC, but not dorsal mPFC, attenuates cue-inducedrelapse to heroin seeking, and has no effect on cue-induced sucroseseeking (Van den Oever et al., 2008). This indicates that ventralmPFC AMPA-R endocytosis specifically mediates relapse to heroinseeking. Notably, cue-evoked changes in levels of GluA2/3 AMPA-Rs occurred both following abstinence as well as after extinctiontraining, indicating that they were not the result of extinctionlearning. Possibly related to the endocytosis of AMPA-Rs in theventral mPFC, we found that re-exposure to heroin-conditionedcues results in an increase in expression of Arc in this brain region(Koya et al., 2006). Arc transcripts are rapidly transported tosynaptic sites (Steward et al., 1998) where they can reduce theamplitude of synaptic GluA2/3-containing AMPA-R currents (RialVerde et al., 2006) by increasing the rate of AMPA-R endocytosis(Chowdhury et al., 2006). Although the induction of Arc duringcue-induced heroin seeking may provide a mechanism to initiate

or maintain elevated rates of GluA2/3 AMPA-R endocytosis, itsdirect role remains to be determined.

To conclude, cue-induced relapse to heroin seeking depends onsynaptic depression in the ventral mPFC caused by acuteendocytosis of GluA2/3 AMPA-R subunits. Decreased synapticstrength in ventral mPFC pyramidal neurons suggests that theexcitability of these neurons is reduced during cue-induced drugseeking. In turn, this suggests that excitatory output from theventral mPFC is diminished during cue-induced relapse to heroinseeking, in line with ventral mPFC inactivation-enhanced drugseeking after extinction learning (Peters et al., 2008; Schmidt et al.,2005). A similar mechanism may occur in the NA shell, as it wasfound that disruption of GluA2 internalization attenuates cocaine-primed reinstatement of drug seeking (Famous et al., 2008).Hence, reduced glutamatergic transmission in the ventral mPFCand NA shell facilitates drug seeking, supporting the observationthat a glutamatergic projection from the ventral mPFC to the NAshell exerts inhibitory control over responding to drug-condi-tioned stimuli (Peters et al., 2008).

7. Clinical implications and future perspectives

Substantial evidence indicates that glutamatergic output fromthe dorsal mPFC to the NA core drives reinstatement of drugseeking (Kalivas et al., 2005; LaLumiere and Kalivas, 2008;McFarland et al., 2003). In addition, a growing body of literaturesuggests that the ventral mPFC suppresses conditioned drugseeking and that reduced functioning of this brain area results inrelapse. Hence, whereas the dorsal mPFC output drives relapse,diminished output from the ventral mPFC may contribute to drugseeking by impairing the ability to actively inhibit responding todrug-conditioned stimuli (Jentsch and Taylor, 1999). Assumingthat the molecular and cellular mechanisms of stimulus-induceddrug seeking in animal models resemble those of relapse inhumans, the findings reviewed here may have several clinicalimplications. In general, (pharmaco)therapy aimed at reducingdorsal mPFC glutamatergic output to the NA core upon drug- orcue-exposure may help to reduce relapse rates in human addicts.As mentioned above, reduced basal extracellular glutamate levelsin the NA augments glutamatergic transmission at mPFC-NAsynapses during reinstatement. Treatment of animals with N-acetylcysteine or ceftriaxone prevents reinstatement of cocaineand heroin seeking (Baker et al., 2003; Sari et al., 2009; Zhou andKalivas, 2008), presumably by restoring levels of the glialglutamate transporter (GLT-1) (Knackstedt et al., 2009) andthereby glutamatergic tone on mGluA2/3 receptors expressed onPFC terminals within the NA (Peters and Kalivas, 2006). In line withthis finding, N-acetylcysteine treatment reduces drug craving andcocaine use in human addicts (LaRowe et al., 2007; Mardikian etal., 2007). Therapy aimed at reducing the excitability of dorsalmPFC pyramidal neurons may also reduce relapse susceptibility byultimately reducing glutamate release within the NA core. Forinstance, stimulation of dopaminergic signaling through D2receptors might restore dopaminergic tone in the mPFC duringabstinence, thereby reducing responsivity of dorsal mPFC pyr-amidal neurons to drug exposure or drug-associated stimuli duringabstinence. However, activation of D2 receptors in brain regionsother than the mPFC may produce side-effects. Normalization ofAGS3 expression might be a more specific target to restore D2signaling and to reduce glutamatergic output from the mPFC inabstinent addicts. In contrast, enhancement of glutamatergictransmission in the ventral mPFC may help to suppress drugseeking responses upon exposure to drug-conditioned stimuli. Inparticular, the heroin relapse associated increase in AMPA-Rendocytosis might be a selective target to prevent cue-inducedrelapse. Agents that are able to specifically reduce regulated, but


not constitutive, endocytosis of post-synaptic AMPA-Rs may exerttheir effect when addicts encounter drug-associated cues and bewithout effect under normal conditions. Further research isnecessary to verify whether small synthetic peptides like TAT-GluR23y or other compounds that inhibit regulated AMPA-Rendocytosis can be used clinically as an anti-relapse agent.

Although great progress has been made in the elucidation of therole of the mPFC in conditioned drug seeking, future research facesseveral challenging issues to gain more insight in the neurobio-logical mechanisms by which mPFC neurons control relapsebehavior. First, it is important to determine whether mPFC controlover cocaine and heroin seeking generalizes to other drugs ofabuse, such as nicotine and alcohol. The majority of the studiesdiscussed here examined the role of the mPFC in relapse to cocaineseeking and to some extent to heroin seeking. Although the ventralmPFC suppresses reinstatement of cocaine seeking after extinctionlearning has occurred, it is not clear whether this extinctionfunction generalizes to other drugs of abuse. Our observation thatsynaptic AMPA-R expression is reduced when a relapse test isperformed after both abstinence and extinction of heroin SA (Vanden Oever et al., 2008), suggests that the ventral mPFC may alsocontrol cue-conditioned heroin seeking after abstinence.

Second, it is crucial to gain better insight in the neuronalsubtypes (e.g. pyramidal neurons versus GABAergic interneurons)that show altered activity patterns during relapse tests and todetermine the efferent brain structures that are affected by alteredoutput from the mPFC. Pharmacological disconnection procedures,electrophysiology approaches and the use of neuronal activitymarkers combined with neuron-specific markers and/or anatomi-cal tracers are valuable tools to address these questions.

Last, a dissociation between the dorsal and ventral mPFC shouldbe made in the analysis of neuroadaptations that result fromrepeated drug exposure. The development of sensitive high-throughput genomics and proteomics technology, as well assophisticated molecular imaging tools allow the analysis of drug-induced adaptations at the (sub)cellular level and will thereforecontribute significantly to the understanding of neuroadaptationsthat maintain relapse vulnerability. Moreover, it is important toinvestigate whether drug-induced neuroadaptations in the mPFCspecifically control drug relapse, or whether they mediateresponding to motivationally relevant events in general.

A better understanding of the maladaptive functioning of mPFCneurons after drug exposure and identification of novel treatmenttargets is crucial for the development of pharmacotherapy that isable to reduce relapse susceptibility, without reducing themotivation for natural rewarding stimuli.

Acknowledgements

The authors thank Dr. J. Peters for helpful comments on themanuscript. MCVDO is supported by an EMBO Fellowship.

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Prefrontal cortex plasticity mechanisms in drug seeking and relapse