Psychostimulant-Induced Neuroadaptations in Nucleus Accumbens …perspectivesinmedicine.cshlp.org/content/3/2/a012021... · 2013-01-31 · Psychostimulant-Induced Neuroadaptations

Psychostimulant-Induced Neuroadaptationsin Nucleus Accumbens AMPA ReceptorTransmission

R. Christopher Pierce1 and Marina E. Wolf2

1Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at theUniversity of Pennsylvania, Philadelphia, Pennsylvania 19104

2Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago,Illinois 60064

Correspondence: [email protected]

Medium spiny neurons of the nucleus accumbens serve as the interface between cortico-limbic regions that elicit and modulate motivated behaviors, including those related to drugsof abuse, and motor regions responsible for their execution. Medium spiny neurons areexcited primarily by AMPA-type glutamate receptors, making AMPA receptor transmissionin the accumbens a key regulatory point for addictive behaviors. In animal models of cocaineaddiction, changes in the strength of AMPA receptor transmission onto accumbens mediumspiny neurons have been shown to underlie cocaine-induced behavioral adaptations relatedto cocaine seeking. Here we review changes in AMPA receptor levels and subunit compo-sition that occur after discontinuing different types of cocaine exposure, as well as changeselicited by cocaine reexposure following abstinence or extinction. Signaling pathways thatregulate these cocaine-induced adaptations will also be considered, as they represent po-tential targets for addiction pharmacotherapies.

Functionally relevant changes in nucleus ac-cumbens glutamatergic transmission in-

duced by psychostimulants (i.e., amphetamineor cocaine) were first identified in the 1990s fol-lowing two scientific advances: (1) the develop-ment of relatively selective AMPA/kainate andNMDA receptor antagonists (Wong et al. 1986;Honore et al. 1988), and (2) a greater apprecia-tion of the influence of glutamatergic afferentsto the nucleus accumbens (Albin et al. 1989;Alexander et al. 1990). Studies on the effects ofpsychostimulants on glutamate transmissionwere also driven by the realization that the reg-

ulated trafficking of glutamate receptors in andout of synapses is a majorcontributor to changesin synaptic strength during hippocampal synap-tic plasticity (Malinow and Malenka 2002).

Early studies of glutamate’s role in psycho-stimulant addiction focused primarilyon a formof psychostimulant-induced neuronal and be-havioral plasticity known as behavioral sensiti-zation wherein repeated exposure to psycho-stimulants (usually in the form of experimenter-delivered injections) results in a progressive andenduring enhancement of psychostimulant-in-duced behavioral responses. By the early 1990s,

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strong evidence had accumulated to support arequirement for glutamate transmission in thedevelopment of behavioral sensitization (Wolf1998). Shortly thereafter, it was found that ad-ministration of AMPA/kainate receptor antag-onists into the core subregion of the nucleusaccumbens attenuated the expression of psy-chostimulant behavioral sensitization, whereasmicroinjection of AMPA into the accumbenscore produced greater hyperactivity in cocaine-pretreated rats (Pierce et al. 1996). Althoughsubsequent work indicated that the role ofAMPA receptor transmission in behavioral sen-sitization is more complex than was originallyappreciated (Bachtell et al. 2008; Ferrario et al.2010; Wolf and Ferrario 2010; Kourrich et al.2012), these initial studies laid the groundworkfor increasingly sophisticated cellular, molec-ular, neurochemical, and electrophysiologicalstudies aimed at defining the role of accumb-al glutamate transmission in psychostimulantaddiction. This review focuses on psychostimu-lant-induced changes in glutamatergic trans-mission in the nucleus accumbens with a par-ticular emphasis on changes in nucleus accum-bens AMPA receptor number and function re-sulting from repeated exposure to cocaine.

CHRONIC COCAINE, SYNAPTIC ANDNONSYNAPTIC GLUTAMATE, AND AMPARECEPTOR EXPRESSION IN THE NUCLEUSACCUMBENS

Microdialysis studies revealed that repeated ex-posure to cocaine followed by a drug-free peri-od resulted in reduced basal extracellular gluta-mate levels in the nucleus accumbens coreowing to decreased activity of the cystine-gluta-mate antiporter (Pierce et al. 1996; Baker et al.2002; Baker et al. 2003). These changes are func-tionally relevant in that administration of N-acetylcysteine, a cystine prodrug that increasesactivity of the cystine-glutamate antiporter, pre-vented the reinstatement of drug seeking in-duced by a priming injection of cocaine (Bakeret al. 2003). This line of work, which has sinceled to clinical trials assessing the effect of N-ace-tylcysteine on cocaine craving in humans (La-Rowe et al. 2007; Mardikian et al. 2007), was

among the first to indicate that repeated cocaineresulted in changes in accumbens glutamater-gic transmission that influenced drug-seekingbehavior (Kalivas et al. 2005). In addition tothe microdialysis studies mentioned above,which showed changes in nonsynaptic gluta-mate pools, other results suggested decreasedactivity of glutamatergic afferents to the nucleusaccumbens during cocaine withdrawal (Ham-mer and Cooke 1994; Goldstein and Volkow2002; Sun and Rebec 2006; Porrino et al. 2007).In addition, electrophysiological studies showedthat repeated cocaine exposure decreased the in-trinsic excitability of accumbens neurons by al-tering voltage-gated conductances (Zhang et al.1998, 2002; Hu et al. 2004, 2005; Dong et al.2006; Ishikawa et al. 2009; Kourrich and Thomas2009; Mu et al. 2010). Each of these three adap-tations—decreased nonsynaptic glutamate, de-creased activity of glutamatergic afferents, anddecreased intrinsic excitability—has the poten-tial to result in a compensatory increase in glu-tamate receptor expression in the accumbens(for a critical evaluation of the role of each ad-aptation see Wolf 2010a). Indeed, a growing lit-erature indicates that repeated contingent ornoncontingent exposure to cocaine followedby an abstinence period is associated with in-creased expression of AMPA receptor subunitsin the nucleus accumbens (for a review, seeSchmidt and Pierce 2010; Wolf and Ferrario2010; Wolf and Tseng 2012). Consistent withthese findings, repeated cocaine administrationhas been reported to augment AMPA receptor-mediated synaptic transmission in the nucleusaccumbens (Kourrich et al. 2007; Conrad et al.2008; Ortinski et al. 2012).

Multiple subtypes of AMPA receptors withdistinct channel properties and pharmacologi-cal profiles are composed from different com-binations of subunits termed GluA1-4, as wellas auxiliary subunits (transmembrane AMPAreceptor regulatory proteins, or TARPs, and cor-nichon-like proteins) that modulate AMPA re-ceptor trafficking and channel function (Strauband Tomita 2011). All AMPA receptors, regard-less of subunit composition, are permeable tosodium and potassium. However, a profounddifference in AMPA receptor channel properties

R.C. Pierce and M.E. Wolf

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results when the GluA2 subunit is absent fromthe tetrameric receptor. This reflects the factthat GluA2 RNA undergoes an editing process,whereby the conversion of a neutral glutaminecodon (Q) to a positively charged arginine (R)renders the channel impermeable to calcium.Because most GluA2 subunits are edited inthis manner, GluA2-containing AMPA recep-tors are primarily calcium impermeable (Tana-ka et al. 2000), and will be referred to herein ascalcium-impermeable AMPA receptors (CI-AMPARs). In contrast, GuA2-lacking AMPA re-ceptors are calcium-permeable AMPA receptors(CP-AMPARs). Relative to CI-AMPARs, CP-AMPARs have larger single channel conduc-tance and faster kinetics, are influenced by dif-ferent pharmacological agents, and display in-ward rectification owing to voltage-dependentblock by endogenous polyamines. CP-AMPARsynaptic incorporation is highly regulated andplays an important role in increased synapticstrength associated with several forms of neuro-nal plasticity (Cull-Candy et al. 2006; Isaac et al.2007; Liu and Zukin 2007; Lee 2012).

In the nucleus accumbens of drug-naıve ro-dents, CP-AMPARs are a minority, accountingfor only 5%–10% of evoked excitatory postsyn-aptic current (EPSC) amplitude (Conrad et al.2008). The predominant CI-AMPARs are com-prised mainly of GluA1A2-containing recep-tors, although GluA2A3-containing receptorsare also present (Reimers et al. 2011). However,as outlined in detail below, extended access co-caine self-administration, but apparently notother types of cocaine regimens, leads to a sub-stantial increase in the synaptic levels of CP-AMPARs in the nucleus accumbens, such thatthey account for approximately 30% of evokedEPSC amplitude after a month or so of with-drawal (Conrad et al. 2008; Mameli et al. 2009;for a review, see Wolf and Tseng 2012).

AMPA RECEPTOR TRAFFICKING ANDCOCAINE-INDUCED PLASTICITY

A growing body of evidence indicates that ac-cumbal AMPA receptors contribute significant-ly to the reinstatement of cocaine seeking, ananimal model of relapse. Thus, administration

of AMPA directly into the nucleus accumbenspromotes reinstatement of cocaine seeking,whereas intra-accumbal administration of anAMPA receptor antagonist blocks reinstatementinduced by a systemic priming injection of co-caine (Cornish et al. 1999; Cornish and Kalivas2000; Suto et al. 2004; Kruzich and Xi 2006;Ping et al. 2008) or cues previously pairedwith cocaine (Backstrom and Hyytia 2007). Al-though most of these microinjection studies didnot directly compare core and shell subregionsof the nucleus accumbens, there is evidence thatincreased glutamate transmission in both thecore and shell contributes to the reinstatementof cocaine seeking. Increased extracellular glu-tamate release in the nucleus accumbens corewas observed during cocaine priming-inducedreinstatement of drug seeking (McFarland et al.2003), whereas administration of an AMPA re-ceptor antagonist into the accumbens shell in-hibited the reinstatement of cocaine seekingprompted by administration of cocaine intothe medial prefrontal cortex (Park et al. 2002).Subsequent findings indicated that administra-tion of an AMPA receptor antagonist into theaccumbens core or shell attenuated the rein-statement of cocaine seeking (Famous et al.2008). Consistent with these results, microin-jection of AMPA directly into the accumbenscore or shell reinstates cocaine seeking (Pinget al. 2008). Taken together, these findings clear-ly indicate that increased transmission throughAMPA receptors in both of the major subre-gions of the nucleus accumbens promotes thereinstatement of cocaine seeking. In addition toresults in reinstatement models, AMPA receptortransmission in the accumbens is also requiredfor drug seeking under second-order schedulesof reinforcement (Di Ciano and Everitt 2001,2004) and for cue-induced seeking after pro-longed abstinence (Conrad et al. 2008; but seealso See et al. 2007).

The findings outlined above raise the possi-bility that cocaine exposure alters AMPA recep-tor levels in nucleus accumbens synapses. Thefirst study to provide direct support for this idearevealed that the ratio of cell-surface to intra-cellular GluA1 and GluA2/3 (identified with anantibody that recognized both subunits) in the

Neuroadaptations in Nucleus Accumbens AMPA

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accumbens was increased 3 weeks, but not 1 day,after discontinuing a sensitizing regimen of re-peated intraperitoneal (i.p.) cocaine injections(Boudreau and Wolf 2005). A number of studieshave confirmed this finding and investigatedthe underlying mechanisms of AMPA receptorredistribution, with ERK emerging as a leadingcandidate but other signaling pathways alsoimplicated (Boudreau et al. 2007, 2009; Schu-mann and Yaka 2009; Pascoli et al. 2011; Schier-berl et al. 2011). Here, we will focus on mech-anisms underlying changes in AMPA receptorsubunit trafficking in the nucleus accumbensafter self-administered cocaine. The next two sec-tions outline the roles of GluA1- and GluA2-containing AMPA receptors, respectively, inadaptations related to cocaine seeking duringwithdrawal. GluA1 and GluA2 are consideredseparately, even though they can obviously becolocalized in the same tetrameric receptor(i.e., the GluA1A2-containing CI-AMPARsthat predominate in the nucleus accumbens ofdrug-naıve animals and after most types of co-caine exposure), because their carboxyl terminidiffer with respect to phosphorylation sites andprotein–protein interaction domains that influ-ence receptor trafficking (Derkach et al. 2007;Shepherd and Huganir 2007; Anggono and Hu-ganir 2012).

NUCLEUS ACCUMBENS GluA1-CONTAINING AMPA RECEPTORSAND THE REINSTATEMENT OFCOCAINE SEEKING

GluA1 subunits play a particularly prominentrole in the reinstatement of cocaine seeking.Suppression of GluA1 transcription in eitherthe accumbens core or shell impaired the rein-statement of drug seeking induced by a cocainepriming injection (Ping et al. 2008). In addi-tion, viral-mediated overexpression of pore-dead GluA1 subunits in the accumbens shellattenuated cocaine reinstatement (White et al.2012). In contrast, when pore-dead GluA1 wasoverexpressed in the accumbens core the rein-statement of cocaine seeking was enhanced(Bachtell et al. 2008). This latter finding, how-ever, is difficult to reconcile with compelling

evidence that AMPA receptor transmission inthe nucleus accumbens core, which is mediatedprimarily by GluA1A2-containing receptors(Reimers et al. 2011), is required for cocaineseeking (Kalivas and Volkow 2005; Wolf and Fer-rario 2010). Overall, we suggest that these stud-ies, especially when combined with evidencefor posttranslational modification of GluA1during reinstatement (see below), suggest thatincreased transmission through GluA1-con-taining AMPA receptors in both the core andshell of the nucleus accumbens promotes thereinstatement of cocaine-seeking behavior (An-derson et al. 2008).

Reinstatement experiments typically use ashort access paradigm in which rats self-admin-ister cocaine 2 h/d for 2–3 wk, followed by ex-tinction. Interestingly, when daily cocaine expo-sure is extended to 6 h and followed by a periodof withdrawal (rather than extinction training),cue-induced cocaine seeking progressively in-tensifies (or “incubates”) over the first severalmonths of withdrawal (Grimm et al. 2001; Pick-ens et al. 2011). Following 45 d of withdrawalfrom 10 d of extended access cocaine self-ad-ministration, Conrad et al. (2008) found an in-crease in cell surface GluA1, but not GluA2, inthe nucleus accumbens compared to either sa-line controls or cocaine-exposed rats tested onwithdrawal day 1. GluA3 was also increased, butthis was observed in cocaine-exposed rats onboth withdrawal days 1 and 45, leaving openthe question of whether GluA3 contributesto withdrawal-dependent changes in synaptictransmission and craving. Parallel electrophysi-ological studies showed inward rectification ofevoked AMPA receptor EPSCs, a hallmark ofCP-AMPARs, in cocaine-exposed rats recordedon withdrawal days 42–47 (Conrad et al. 2008).These biochemical and electrophysiologicalresults indicated an increase in CP-AMPARs(GluA1 homomers or GluA1A3 receptors) inaccumbens synapses after prolonged withdraw-al. Supporting the functional significance ofthese findings, injection of the CP-AMPARantagonist NASPM into the accumbens coreon withdrawal day 45 blocked the expressionof incubated cue-induced cocaine seeking. Col-lectively, these findings suggest that synaptic



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incorporation of CP-AMPARs translates intoenhanced drug seeking, although whether thisis a consequence of enhanced calcium signalingor other differences (e.g., larger single channelconductance) is unclear (Conrad et al. 2008;Wolf and Tseng 2012).

Subsequent work confirmed the presenceof CP-AMPARs in the accumbens core after ex-tended access cocaine self-administration (Fer-rario et al. 2011a; McCutcheon et al. 2011a,b)and showed that CP-AMPARs also accumu-late in the shell subregion (Mameli et al.2009; McCutcheon et al. 2011b). In addition,time course studies have shown that CP-AM-PARs are first detected after approximately amonth of withdrawal from extended access co-caine self-administration (Wolf and Tseng2012). Thus, other mechanisms must be re-sponsible for the expression of incubated co-caine craving at earlier withdrawal times. Thereason for the delay in CP-AMPAR accumula-tion is unclear, although one contributing fac-tor may be a slowly developing withdrawal-de-pendent decrease in surface expression ofmGluR1. Because mGluR1 normally exerts abraking influence on CP-AMPAR accumula-tion, loss of mGluR1 tone may help enableCP-AMPAR accumulation during withdrawal(Loweth et al. 2012). Once CP-AMPARs are pre-sent, they remain in nucleus accumbens synaps-es at least through withdrawal day 70, makingthis a very persistent form of plasticity that likelycontributes to protracted risk of relapse (Wolfand Tseng 2012).

Recently, whole cell patch clamp recordingsshowed that CP-AMPAR accumulation in thenucleus accumbens is specifically linked to ex-tended access cocaine self-administration, asit does not occur in rats treated with experi-menter-delivered cocaine (McCutcheon et al.2011b) or following limited access cocaineself-administration (Purgianto et al. 2012).These results do not, however, preclude the pos-sibility of CI-AMPAR up-regulation after limit-ed access cocaine self-administration. Indeed,a recent study found increased mEPSC ampli-tude and AMPA/NMDA ratios in the nucleusaccumbens shell after 3–4 wk, but not 1–2 d,of abstinence from a limited access regimen

(Ortinski et al. 2012). Together, these studies in-dicate a withdrawal-dependent increase in syn-aptic levels of CI-AMPARs after limited accesscocaine self-administration. Consonant withthese findings, long-term potentiation (LTP)but not long-term depression (LTD) is impairedin the nucleus accumbens on withdrawal day 21after limited access cocaine self-administration(Knackstedt et al. 2010). The results of Ortinskiet al. (2012) suggest that this may reflect occlu-sion of LTP by prior AMPA receptor up-regula-tion. However, as discussed elsewhere in detail(Wolf 2010a; Wolf and Ferrario 2010), the liter-ature on induction of LTP or LTD after cocaineexposure is full of contradictions. In many cases,this may be attributed to the fact that plasticitywas assessed at short withdrawal times whenAMPA receptor levels were in flux. For this andmany other reasons, it can be problematic toinfer AMPA receptor levels from changes in theability to elicit LTP or LTD following cocaineexposure.

The carboxy-terminal region of the GluA1subunit contains all of the known protein phos-phorylation sites, including serines phosphory-lated by cyclic AMP-dependent protein kinase(PKA), protein kinase C (PKC), and/or calci-um/calmodulin-dependent protein kinase II(CaMKII) (Derkach et al. 2007; Shepherd andHuganir 2007; Anggono and Huganir 2012).Stimulation of D1 dopamine receptors in thenucleus accumbens promotes cocaine reinstate-ment by activating Gs/adenylyl cyclase/cAMP(Schmidt and Pierce 2006; Schmidt et al. 2006).D1 dopamine receptor stimulation of cAMP re-sults in the activation of PKA, which is linked tococaine seeking (Self et al. 1998) and, based onwork in cultured accumbens neurons, increasesthe insertion of GluA1-containing AMPA re-ceptors into the plasma membrane (Chaoet al. 2002a,b; Mangiavacchi and Wolf 2004a).Moreover, repeated exposure to cocaine en-hances enzyme activity of PKA in the nucleusaccumbens of rodents (Terwilliger et al. 1991;Lu et al. 2003). No changes in total GluA1-pSer845 (PKA phosphorylation site) were ob-served during the reinstatement of cocaine seek-ing (using a short access paradigm) (Andersonet al. 2008). However, it was recently shown that



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surface expression of GluA1-pSer845 was in-creased in the nucleus accumbens 35 days fol-lowing cocaine self-administration (using along access paradigm) (Ferrario et al. 2011a),which may prime accumbens AMPA receptorsfor synaptic insertion (Sun et al. 2005, 2008;Gao et al. 2006; Oh et al. 2006; Man et al.2007; for a review, see Wolf 2010b). Direct inter-actions between PKA and GluA1 during cocaineself-administration and subsequent cocaineseeking clearly need to be examined in greaterdetail.

Another target of PKA is the L-type calciumchannel, which plays a critical role in psycho-stimulant-induced behavioral and neuronalplasticity (Gnegy 2000; Licata and Pierce 2003;Rajadhyaksha and Kosofsky 2005). Calcium in-flux through L-type channels activates a familyof protein kinases including CaMKII, an en-zyme that plays a critical role in several formsof neuronal plasticity including changes in-duced by repeated cocaine exposure (Licataand Pierce 2003; Giordano et al. 2010; Lowethand Vezina 2011). Recent work specifically im-plicates CaMKII in nucleus accumbens AMPAreceptor plasticity produced by repeated non-contingent psychostimulant exposure (Bou-dreau et al. 2009; Loweth et al. 2010; Schierberlet al. 2011) as well as motivation to self-admin-ister amphetamine (Loweth et al. 2008, 2010).After cocaine self-administration, stimulatingD1-like dopamine receptors in the medialnucleus accumbens shell promotes the rein-statement of cocaine seeking by serially stimu-lating L-type calcium channels and phosphor-ylation of CaMKII (Anderson et al. 2008).Furthermore, reinstatement of cocaine-seek-ing behavior was associated with an increasein phosphorylation of GluA1-pSer831, a sitephosphorylated by CaMKII and PKC, and en-hanced cell-surface expression of GluA1-con-taining AMPA receptors in the accumbens shell(Anderson et al. 2008). Consistent with thesefindings, impairing the trafficking of GluA1-containing AMPA receptors to the cell surfacewithin the nucleus accumbens shell attenuatedthe ability of a priming injection of cocaineto reinstate drug-seeking behavior (Andersonet al. 2008). These results indicate that D1-like

dopamine receptor stimulation-dependent ac-tivation of L-type calcium channels and CaM-KII facilitates the reinstatement of cocaine seek-ing by promoting the synaptic incorporation ofGluA1-containing AMPA receptors in the nu-cleus accumbens shell. Thus, CaMKII activity inthe nucleus accumbens shell may be an essentiallink between dopamine and glutamate systemsinvolved in the neuronal plasticity underlyingcocaine craving and relapse.

Anderson et al. (2008) used a limited accesscocaine self-administration regimen, which doesnot lead to persistent CP-AMPAR accumulationin the nucleus accumbens (see previous section).Therefore, the CaMKII-dependent increase inGluA1 surface expression may primarily reflectan increase in GluA1A2 receptors. Alternatively,it could involve insertion of homomeric GluA1CP-AMPARs, given that CP-AMPARs are presentin the nucleus accumbens of drug-naıve rats,albeit at low levels, in homogenates (Reimerset al. 2011), synapses (Conrad et al. 2008), andin extrasynaptic AMPA receptor pools that sup-ply the synapse (Ferrario et al. 2011b). A rela-tionship between CP-AMPARs and CaMKIImay also be suggested by an increased ratio ofphosphorylated to total CaMKII in the accum-bens on withdrawal day 45, but not withdrawalday 1, after extended access cocaine self-admin-istration, in concert with CP-AMPAR accumu-lation (Ferrario et al. 2011a). However, it is notclear whether CaMKII activation helped to pro-mote CP-AMPAR accumulation or whetherCaMKII activation on withdrawal day 45 wassecondary to CP-AMPAR accumulation, be-cause CP-AMPARs would represent a newsource of calcium influx into the medium spinyneuron, which could underlie persistent activa-tion of CaMKII signaling. Increased ERK acti-vation was also observed in conjunction withCP-AMPAR synaptic accumulation (Ferrarioet al. 2011a).

Although the CaMKII signaling pathwayclearly plays a role in cocaine reinstatement inthe accumbens shell, the specific role of CaMKIIphosphorylation in GluA1 subunit traffick-ing remains an area of active study. Early stud-ies examining CaMKII involvement in AMPAreceptor synaptic delivery in hippocampus



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indicated that increasing CaMKII activity en-hanced insertion of GluA1 subunits into syn-apses; however, this effect was not influenced bymutating the GluA1 Ser831 residue (Hayashiet al. 2000). This result indicated that CaMKIIsubstrates other than GluA1 influence the traf-ficking of AMPA receptors. Stargazin, a mem-ber of the family of transmembrane AMPA re-ceptor regulatory proteins (TARPs) that serveas AMPA receptor auxiliary subunits, is nowconsidered the strongest candidate. CaMKIIphosphorylation of stargazin enables it to inter-act with PSD95 and thus immobilize AMPAreceptors at the synapse (for a review, see Lis-man et al. 2012). The interactions amongCaMKII, stargazin, and other potentially im-portant CaMKII substrates (i.e., SAP97) thatmay influence the trafficking of GluA1 subunitsduring cocaine reinstatement remain to be ex-amined in detail. However, the TARP g4, as wellas stargazin, have been implicated in CP-AM-PAR accumulation after prolonged withdrawalfrom extended access cocaine self-administra-tion (Ferrario et al. 2011b), suggesting TARPsas players in cocaine-induced neuroadapta-tions.

The data summarized in this section indi-cate that repeated cocaine exposure promotesthe synaptic expression of GluA1-containingAMPARs in core and shell subregions of thenucleus accumbens. After noncontingent co-caine self-administration, GluA1A2-containingAMPA receptors, the predominant AMPA re-ceptor type in the accumbens, are up-regulated.After extended access cocaine self-administra-tion, levels of GluA1-containing CP-AMPARsare increased after approximately a month ofwithdrawal and then remain in synapses. Al-though limited access cocaine self-administra-tion leads to increased synaptic levels of CI-AM-PARs but not CP-AMPARs during withdrawal, asubsequent cocaine challenge injection rapidlyincreases the surface expression of GluA1, po-tentially indicating up-regulation of either CP-AMPARs or GluA1A2-containing CI-AMPARs.The next section will consider growing evidencefor the specific regulation of the GluA2 subunitin the nucleus accumbens of cocaine-exposedanimals.

NUCLEUS ACCUMBENS GluA2 AMPARECEPTOR SUBUNIT TRAFFICKINGAND THE REINSTATEMENT OFCOCAINE SEEKING

PKC phosphorylation of GluA2 subunits atSer880 influences the trafficking of GluA2-con-taining AMPA receptors (Song and Huganir2002; Shepherd and Huganir 2007). The sameregion of the GluA2 carboxyl terminus is re-quired for interactions with glutamate receptorinteracting protein 1 (GRIP1) and protein in-teracting with C kinase 1 (PICK1), two impor-tant proteins for AMPA receptor trafficking.Based on studies of hippocampal and cerebellarLTD, a model has been developed whereby PKCphosphorylation of GluA2 at Ser880 leads to de-tachment from GRIP1 and increased associationwith PICK1, resulting in an increased rate of in-ternalization. However, other evidence supportsalternative functions for GRIP1 and PICK1, in-cluding different interactions of PICK1 in reg-ulating trafficking of CI-AMPARs versus CP-AMPARs (Anggono and Huganir 2012).

Although the literature is not extensive, pre-vious studies have shown a role for PKC in psy-chostimulant-mediated behaviors. For exam-ple, repeated cocaine administration increasesthe phosphorylation of some, but not all, iso-forms of PKC in the nucleus accumbens (Ste-ketee et al. 1998; Chen et al. 2007). Behavioralexperiments indicated that intra-accumbal ad-ministration of a PKC inhibitor attenuatedamphetamine-mediated conditioned place pre-ference (CPP) (Aujla and Beninger 2003) andsystemic administration of a PKC inhibitorattenuated cocaine-induced CPP (Cervo et al.1997). Similarly, administration of a PKCinhibitor directly into the accumbens blockedthe expression of cocaine-induced behavioralsensitization (Pierce et al. 1998). In terms ofthe reinstatement of cocaine seeking, increasedphosphorylation of GluA2 Ser880 (PKC site)was observed during priming-induced rein-statement, whereas administration of a peptideinto the nucleus accumbens shell that inhibitsGluA2-PICK1 interactions attenuated cocaine-seeking behavior (Famous et al. 2008). Basedon the results summarized in the previous



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paragraph, these results suggest that impairingthe endocytosis of GluA2-containing AMPA re-ceptors in the nucleus accumbens disrupts thereinstatement of drug seeking. Combined withresults showing increased GluA1 surface expres-sion 30 min after cocaine-primed reinstatement(Anderson et al. 2008; previous section), thesefindings suggest the possibility that a rapid ex-change between a GluA1-containing popula-tion of AMPA receptors and a GluA2-contain-ing population of AMPA receptors occurs inconcert with cocaine-induced reinstatement.

Activation of a number of receptor subtypesincreases the activation of PKC. For example,group I metabotropic glutamate receptors (i.e.,mGluR1, mGluR5) signal through PKC (Conn2003) and these receptors play a significant rolein cocaine-induced neuroadaptations and be-havioral responses (Olive 2009). Initial evidenceindicating that repeated cocaine injections in-creased mGluR5 mRNA levels in the nucleusaccumbens shell (Ghasemzadeh et al. 1999)was followed by the discovery that constitutivemGluR5 receptor knockout mice were insen-sitive to the locomotor stimulant propertiesof cocaine and would not self-administer thispsychostimulant (Chiamulera et al. 2001). Con-sistent with these findings, subsequent workshowed that administration of the mGluR5 re-ceptor antagonists, MPEP or MTEP, decreasedcocaine self-administration (Kenny et al. 2003,2005; Lee et al. 2005; Paterson et al. 2005; Plattet al. 2008) and attenuated the ability of a prim-ing injection of cocaine (Lee et al. 2005; Kumar-esan et al. 2009) or cocaine-associated cues(Backstrom and Hyytia 2006; Kumaresan et al.2009) to reinstate cocaine seeking. Moreover,administration of an mGluR1 antagonist intothe accumbens core, but not the shell, attenuat-ed context-dependent cocaine seeking (Xieet al. 2011) and intra-accumbens shell microin-jection of MPEP attenuated cocaine-inducedreinstatement of drug seeking (Kumaresan etal. 2009).

Stimulation of group I mGluRs activatesphospholipase C (PLC) resulting in the gener-ation of inositol triphosphate (IP3) and diacyl-glycerol (DAG), which activates PKC (Conn andPin 1997; Kim et al. 2008). As would be predict-

ed from the effects of group I mGluR antago-nists described above, recent evidence indicatesthat activation of this signaling pathway con-tributes significantly to the reinstatement of co-caine seeking. Thus, administration of a PLCor PKC inhibitor into the accumbens core orshell dose-dependently attenuated the reinstate-ment of cocaine seeking (Schmidt et al. 2011;Wang et al. 2012). Moreover, intrashell micro-injection of the mGluR1/5 agonist, DHPG(Schmidt et al. 2011), or the mGluR5 agonist,CHPG (Wang et al. 2012), dose-dependentlypromoted the reinstatement of cocaine seeking(in the absence of a cocaine challenge injection).Moreover, the DHPG effect was blocked by pre-treatment with a PKC inhibitor (Schmidt et al.2011).

Taken together, studies with group I ago-nists and antagonists show that activation ofmGluR1/5 receptors and the associated PLC/IP3/DAG/PKC signaling pathway in the nucle-us accumbens promotes the reinstatement ofcocaine seeking. The simplest interpretationof these results is that postsynaptic mGluRscontribute, along with AMPA receptors, to theactivation of medium spiny neurons that is re-quired for reinstatement. One might expect thiseffect to be opposed by the ability of mGluR5stimulation to elicit presynaptically expressedLTD (through a mechanism that depends onretrograde endocannabinoid signaling leadingto activation of CB1 receptors on glutamatenerve terminals) and thereby attenuate excitato-ry synaptic transmission onto medium spinyneurons (Robbe et al. 2002; Lovinger 2008).Perhaps the balance is tipped away from LTDbecause many types of cocaine exposure, evena single i.p. injection (Fourgeaud et al. 2004),blunt or even eliminate this form of mGluR5-LTD in accumbens neurons (Wolf and Tseng2012), although it is not clear how long thisblunting persists after different types of cocaineexposure.

Notably, all studies indicating stimulatoryeffects of group I mGluRs on reinstatement ofcocaine seeking have been conducted after lim-ited access cocaine self-administration. Afterextended access cocaine self-administrationand prolonged withdrawal (.1 mo) leading to



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incubation of cocaine craving, there appearsto be a dramatic rearrangement of interactionsbetween group I mGluRs and AMPA recep-tors. First, CB1R-dependent, presynaptically ex-pressed mGluR5-LTD is eliminated (McCutch-eon et al. 2011a). This is not surprising because,as noted in the previous paragraph, many priorstudies have shown that cocaine exposure bluntsor eliminates mGluR5-LTD in the nucleus ac-cumbens. More strikingly, mGluR1, which hasvery little effect on excitatory synaptic trans-mission in control animals, acquires the abilityto regulate AMPA receptor transmission afterincubation. Thus, bath application of DHPG,in slices from the cocaine-exposed animals, rap-idly eliminated the postsynaptic CP-AMPARcontribution to accumbens synaptic transmis-sion, but enhanced the CI-AMPAR contribution(McCutcheon et al. 2011a). These effects wereblocked by an mGluR1 (but not an mGluR5)antagonist and a PKC inhibitor (McCutcheonet al. 2011a). The most straightforward inter-pretation of these results is that in cocaine ex-perienced rats administration of the mGluR1/5 agonist DHPG to the nucleus accumbensresulted in the mGluR1-dependent endocyto-sis of CP-AMPARs and synaptic insertion ofCI-AMPARs. Consistent with the first part ofthis interpretation, when administered to cul-tured accumbens neurons DHPG promotedthe rapid internalization of GluA1-contain-ing AMPA receptors (Mangiavacchi and Wolf2004b). The latter part may seem inconsistentwith a role for PKC signaling in promoting in-ternalization of CI-AMPARs (Famous et al.2008), but it must be recalled that events down-stream from PKC (e.g., changes in associationbetween GluA2, GRIP1, and PICK1) are verycomplex and can be associated with AMPA re-ceptor insertion as well as removal (see Ang-gono and Huganir 2012).

It is notable that an mGluR1-mediated ex-change of CP-AMPARs for CI-AMPARs hasbeen reported previously in VTA and cerebellarsynapses that contain CP-AMPARs (Belloneand Luscher 2006; Mameli et al. 2007; Kellyet al. 2009; for a review, see Wolf and Tseng2012). In all brain regions, including the nucle-us accumbens, this exchange results in LTD, be-

cause a high conductance CP-AMPAR is beingexchanged for a lower conductance CI-AMPAR.Presumably in these situations, the inhibitoryeffect of removing CP-AMPARs is dominantover any other postsynaptic effects producedby mGluR1 stimulation, so the net effect is at-tenuation of excitatory synaptic transmissionand thus reduced cocaine seeking.

The suggestion that mGluR1 stimulationmight blunt cocaine craving (McCutcheon et al.2011a) appears to be at odds with a substantialliterature indicating that group I mGluR antag-onists attenuate the reinstatement of cocaineseeking (Olive 2009). However, the majority ofthese studies implicated mGluR5. In contrast,DHPG-induced reversal of cocaine-mediatedaccumulation of CP-AMPARs in the nucleusaccumbens was solely owing to activation ofmGluR1 (McCutcheon et al. 2011a). More im-portantly, none of these studies tested cocaineseeking in animals that experienced both ex-tended access cocaine self-administration anda prolonged period of withdrawal (i.e., the cir-cumstances that lead to CP-AMPAR accumula-tion in nucleus accumbens synapses). Once CP-AMPARs are present in nucleus accumbens syn-apses, stimulation of mGluR1, as opposed toblockade of mGluR5, may be a more effectiveway to decrease excitatory transmission in theaccumbens and reduce craving. Indeed, ourpreliminary results suggest that mGluR1 stim-ulation reduces the expression of incubated cue-induced cocaine seeking (JA Loweth and MEWolf, unpubl.).

CONCLUSIONS

AMPA receptor plasticity occurs in the nucleusaccumbens during cocaine withdrawal as wellas in conjunction with the reinstatement ofcocaine-seeking behavior. During withdrawal,AMPA receptor levels in nucleus acumbens syn-apses are increased, but the time course ofAMPA receptor up-regulation and the type ofAMPA receptor affected depend on the cocaineregimen. Noncontingent cocaine exposure leadsto a relatively rapid up-regulation of CI-AM-PARs that is evident by withdrawal day 7, where-as limited access cocaine self-administration



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increases synaptic AMPA receptor levels, butthese appear to be CI-AMPARs rather thanCP-AMPARs. Extended access cocaine self-ad-ministration followed by prolonged withdrawal(.1 mo) leads to a persistent increase in ac-cumbens levels of CP-AMPARs that mediatethe expression of incubated cue-induced co-caine craving. Superimposed on withdrawal-dependent changes, cocaine-primed reinstate-ment after limited access cocaine self-adminis-tration involves removal of GluA2-containingAMPA receptors (Famous et al. 2008; Wigginset al. 2011) and increases in GluA1-mediatedexcitatory transmission in the accumbens shell(Anderson et al. 2008).

The mechanisms that control AMPA recep-tor levels and subtype over the long term, as wellas mechanisms that regulate rapid AMPA recep-tor plasticity in response to cocaine reexposure,are potential targets for anticraving medica-tions. Given the serious side effects associatedwith direct AMPA receptor blockade, it will bemost useful to target mechanisms that indirect-ly regulate synaptic AMPA receptor transmis-sion. Recently acquired information about thesubtypes of AMPA receptors and the regulatorymechanisms that predominate after differenttypes of cocaine exposure can be used to targettherapeutic approaches to specific clinical situ-ations. For example, N-acetyl-cysteine, now inclinical trials, works by targeting adaptationsthat are produced even by noncontingent co-caine exposure (Kalivas 2009) and may, there-fore, have utility in many situations. However,mGluR1 agonists, which normalize a changein synaptic transmission associated with pro-longed withdrawal from extended access cocaineself-administration (i.e., CP-AMPAR accumula-tion), may be useful for users who have achievedabstinence and hope to minimize the likelihoodof cue-induced relapse. The signaling mecha-nisms altered by repeated cocaine exposure arecomplex and involve manyeffectors. As reviewedabove, L-type calcium channel antagonists andtheir associated signaling systems link D1 do-pamine receptors to GluA1-containing AMPAreceptors during the reinstatement of cocaineseeking. Thus, L-type calcium channel antago-nists, which have long been used in the treatment

of hypertension, might also prove to be effica-cious in the treatment of cocaine craving andrelapse. A more complete knowledge of the pre-cise mechanisms underlying cocaine-inducedchanges in AMPA receptor transmission in thenucleus accumbens and other brain regionsholds promise for identifying novel targets forthe development of pharmacotherapies for co-caine addiction, which thus far remain elusive.

ACKNOWLEDGMENTS

The authors received support from DA009621,DA015835, DA029099 (M.E.W.), DA15214,DA18678, DA22339, and DA31535 (R.C.P.). Wethank Dr. Jessica A. Loweth for insightful com-ments on this manuscript.

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December 10, 20122013; doi: 10.1101/cshperspect.a012021 originally published onlineCold Spring Harb Perspect Med

R. Christopher Pierce and Marina E. Wolf AMPA Receptor TransmissionPsychostimulant-Induced Neuroadaptations in Nucleus Accumbens

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the Central Nervous System-Tetrahydrocannabinol in9∆Synaptic Targets of

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Animal Studies of Addictive BehaviorLouk J.M.J. Vanderschuren and Serge H. Ahmed

Translational Research in Nicotine DependenceJill R. Turner, Allison Gold, Robert Schnoll, et al.

Epigenetics and Psychostimulant Addiction

West, et al.Heath D. Schmidt, Jacqueline F. McGinty, Anne E.

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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