Review
AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine

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Abstract

This review focuses on cocaine-induced postsynaptic plasticity in the nucleus accumbens (NAc) involving changes in AMPA receptor (AMPAR) transmission. First, fundamental properties of AMPAR in the NAc are reviewed. Then, we provide a detailed and critical analysis of literature demonstrating alterations in AMPAR transmission in association with behavioral sensitization to cocaine and cocaine self-administration. We conclude that cocaine exposure leads to changes in AMPAR transmission that depend on many factors including whether exposure is contingent or non-contingent, the duration of withdrawal, and whether extinction training has occurred. The relationship between changes in AMPAR transmission and responding to cocaine or cocaine-paired cues can also be affected by these variables. However, after prolonged withdrawal in the absence of extinction training, our findings and others lead us to propose that AMPAR transmission is enhanced, resulting in stronger responding to drug-paired cues. Finally, many results indicate that the state of synaptic transmission in the NAc after cocaine exposure is associated with impairment of AMPAR-dependent plasticity. This may contribute to a broad range of addiction-related behavioral changes.

Introduction

The nucleus accumbens (NAc) occupies a key position in the neural circuitry of motivation and reward (Kelley, 2004) and alterations in this circuitry are believed to underlie drug addiction (Kalivas and Volkow, 2005, Everitt and Robbins, 2005). The majority of NAc neurons (∼90%) are medium spiny GABA neurons (MSN; Meredith and Totterdell, 1999). MSN receive glutamate inputs from cortical and limbic regions important for regulating motivated behaviors, including drug seeking, and their projections influence motor regions important for the execution of motivated behaviors (Groenewegen et al., 1999, Kelley, 1999). Based on this connectivity and functional studies, Mogenson (1987) suggested that the NAc translates “…the motivational determinants of behavior…into actions”. Indeed, in many common experimental situations, the the final common pathway for drug seeking involves glutamate inputs terminating on MSN in the NAc (Kalivas and McFarland, 2003, Kalivas and Volkow, 2005), although motor circuitry involving the dorsal striatum becomes more important as drug use becomes habitual (Everitt and Robbins, 2005). This review will focus specifically on cocaine-induced alterations in glutamate transmission and plasticity involving α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR) in the NAc.

Glutamate inputs acutely excite NAc MSN primarily by activating AMPAR (Pennartz et al., 1990, Hu and White, 1996) and results in many animal models of addiction indicate that AMPAR activation in the NAc is necessary for drug seeking. Thus, intra-NAc infusion of AMPAR antagonists blocks cue-induced cocaine seeking after withdrawal (Conrad et al., 20081), cocaine seeking under second-order schedules of reinforcement (Di Ciano and Everitt, 20012; Di Ciano and Everitt, 20041), cue-induced reinstatement (Bäckstrom and Hyytiä, 20071), and cocaine-primed reinstatement (Cornish and Kalivas, 20003; Famous et al., 20084). Cocaine-primed reinstatement is also blocked by intra-NAc injection of antisense oligonucleotides directed against the AMPAR subunit GluR1 (Ping et al., 20084). Conversely, infusion of AMPA into the NAc reinstates cocaine seeking after extinction (Cornish et al., 19995; Cornish and Kalivas, 20003; Suto et al., 20043; Kruzich and Xi, 20061; Ping et al., 20084). Together, these studies indicate that AMPAR transmission in both core and shell can play a role in cocaine seeking, although core is more important for cue-controlled cocaine seeking, whereas blocking AMPAR transmission in either core or shell prevents cocaine-primed reinstatement (see footnotes for placement of injection cannula in each study; Meredith et al., 2008 for a review of anatomical and functional distinctions between core and shell; and Section 3 for information about animal models).

An important feature of many animal models of addiction is that behavioral responses to cocaine and cocaine-associated cues are strengthened in animals with prior cocaine experience. We hypothesize that this occurs, in part, because additional AMPAR are added to excitatory synapses onto NAc MSN. The addition of AMPAR to MSN synapses will prime these neurons to respond more robustly to glutamate released by cortical and limbic inputs in response to drug and drug-associated cues. This enhanced responding will promote cocaine seeking and affect subsequent cocaine-induced plasticity in the NAc. Our hypothesis is based in part on evidence that AMPAR trafficking into synapses underlies increased synaptic strength in many forms of LTP (Section 2), although we are not equating drug experience with LTP (see Section 7). One major shortcoming of this hypothesis is that it does not take into account the heterogeneity of both NAc MSN and glutamate afferents to the NAc (see Section 1.2). Nevertheless, it provides a useful theoretical framework for interpreting the literature and designing future experiments.

This review will begin by describing fundamental features of AMPAR transmission in the NAc (Section 2) and animal models used for studies of cocaine-induced AMPAR plasticity (Section 3). Then, we will critically evaluate the literature related to our hypothesis, focusing on sensitization to cocaine (Section 4) and cocaine self-administration (Section 5). We will also discuss the effects of cocaine re-exposure after contingent and non-contingent cocaine administration (Section 6) and the effect of cocaine-induced AMPAR adaptations on the ability to elicit subsequent synaptic plasticity in the NAc (Section 7). We conclude with a brief comparison of cocaine and amphetamine (Section 8).

In light of the central role of AMPAR in many forms of experience-dependent plasticity (Kessels and Malinow, 2009), cocaine-induced alterations in AMPAR function would be expected to have widespread consequences by disrupting the normal way that behavior is shaped by experiences related to drugs or natural rewards. Here, we focus on the hypothesis that enhanced AMPAR transmission in the NAc contributes to the pathologically strengthened incentive-motivational properties of drugs and drug-paired cues that characterizes addiction (Robinson and Berridge, 1993, Robinson and Berridge, 2001, Robinson and Berridge, 2008).

A large number of transmitters and signaling pathways have been implicated in addiction-related plasticity (e.g., Thomas et al., 2008). Our hypothesis (AMPAR upregulation contributes to enhanced drug seeking) is narrowly focused on postsynaptic changes in NAc neurons. This piece of the puzzle deserves careful attention based on enormous precedent for a critical role of postsynaptic AMPAR transmission in synaptic plasticity throughout the brain. We hope that a comprehensive review of the AMPAR-related literature will facilitate its integration with studies focusing on DA transmission (Self, 2004, Anderson and Pierce, 2005) as well as other adaptations that regulate the excitability of MSN. Among these other adaptations, two will be discussed briefly because they are expected to work in concert with synaptic AMPAR changes to determine the output of the NAc after repeated cocaine exposure.

First, basal extracellular glutamate levels in the NAc are decreased after both experimenter- and self-administered cocaine due to reduced activity of the cystine–glutamate antiporter (Kalivas, 2009). This has been observed at short (1 day) and long (3 week) withdrawal times (e.g., Miguéns et al., 2008, Baker et al., 2003). A major consequence of the reduction of extracellular glutamate levels is loss of glutamate tone on presynaptic metabotropic glutamate receptors (mGluR2/3) that normally exert a “braking” effect on synaptic glutamate release. Restoring or preventing the decrease in extracellular glutamate levels restores normal regulation of glutamate transmission and decreases cocaine-primed reinstatement of drug seeking (as well as other cocaine-related behaviors), in concert with normalization of many cocaine-induced neuroadaptations in the NAc (Baker et al., 2003, Madayag et al., 2007, Moussawi et al., 2009, Kalivas, 2009). It is notable that all of these studies have been conducted in the core subregion. More recent work has also implicated the glial glutamate transporter GLT-1 in cocaine-induced dysregulation of glutamate transmission (Sari et al., 2009, Knackstedt et al., 2010).

Second, both experimenter- and self-administered cocaine decrease the intrinsic membrane excitability of MSN in the NAc through effects on voltage-sensitive ion channels (Zhang et al., 1998, Zhang et al., 2002, Hu et al., 2004, Hu et al., 2005, Dong et al., 2006, Kourrich and Thomas, 2009, Ishikawa et al., 2009, Mu et al., in press). Most of these studies sampled core and shell during the first several days after discontinuing experimenter-administered cocaine (Zhang et al., 1998, Zhang et al., 2002, Hu et al., 2004, Hu et al., 2005), but some results suggest different effects in core and shell (Kourrich and Thomas, 2009). Decreased intrinsic excitability in NAc shell persists for at least 3 weeks after experimenter-administered cocaine (Ishikawa et al., 2009, Kourrich and Thomas, 2009) but is less persistent if cocaine is self-administered (Mu et al., in press). Together, intrinsic excitability and synaptic strength determine the net output of NAc neurons, so it is important to understand whether changes in these two parameters are interdependent (Ishikawa et al., 2009). Some possible relationships between presynaptic and postsynaptic adaptations are discussed briefly in Section 4.2.

It is notable that AMPAR upregulation, decreased intrinsic excitability and decreased extracellular glutamate levels are probably “global” changes affecting many or all MSN (with caveats about core/shell differences noted above). A role for global NAc plasticity is not incompatible with the abnormal response of human addicts to a broad spectrum of stimuli. However, many recent results emphasize the importance of subpopulations of MSN (“functional ensembles”; Pennartz et al., 1994) that exhibit heterogeneous responses to drugs and drug-paired cues, as well as natural rewards and aversive stimuli, probably due to input-specific regulation (O’Donnell, 2003, Peoples et al., 2007, Goto and Grace, 2008, Mattson et al., 2008, Carlezon and Thomas, 2009, Koya et al., 2009b, Wheeler and Carelli, 2009). Hypotheses must be developed to explain how global changes interact with ensemble-specific changes to selectively enhance particular behaviors (e.g., cocaine-related behaviors). One idea, based on the ability of DA to gate the activation of NAc neurons by glutamate inputs (Nicola et al., 2000, O’Donnell, 2003, Owesson-White et al., 2009), is that DA and other inputs select the population of MSN that is activated in a particular behavioral context, and then global adaptations (e.g., cocaine-induced AMPAR upregulation) influence the strength of that activation and perhaps broaden the population of MSN that is affected (see Section 5.4 for more discussion).

Section snippets

AMPAR and their role in neuronal plasticity

AMPAR mediate the majority of excitatory transmission in the brain. Furthermore, changes in synaptic strength in many forms of plasticity are mediated by AMPAR trafficking in and out of synapses (Carroll et al., 2001, Malinow and Malenka, 2002, Song and Huganir, 2002, Bredt and Nicoll, 2003, Shepherd and Huganir, 2007, Derkach et al., 2007). AMPAR assemble as tetramers (dimers of dimers) from GluR1–4 subunits (Cull-Candy et al., 2006, Greger and Esteban, 2007). Landmark co-immunoprecipitation

Sensitization

The repeated administration of a psychostimulant drug like cocaine produces an enduring hypersensitivity to its psychomotor activating effects, a phenomenon known as psychomotor sensitization (Segal, 1975, Robinson and Becker, 1986). Psychomotor activity includes a variety of behaviors including locomotion and patterned, repetitive movements (stereotyped behaviors) such as head and limb movements, sniffing and rearing. These behaviors occur to varying degrees depending on a number of factors

AMPAR surface and synaptic expression in the NAc after withdrawal from a sensitizing cocaine regimen

To test the hypothesis that AMPAR trafficking is associated with locomotor sensitization, we developed a protein crosslinking assay that enables the detection of changes in cell surface and intracellular protein pools resulting from in vivo treatments. This assay uses BS3, a bi-functional crosslinking reagent that does not cross cell membranes and therefore crosslinks cell surface proteins into high molecular weight aggregates, whereas intracellular proteins are unmodified. Surface and

Cocaine challenge reverses AMPAR upregulation in cocaine-sensitized rodents

When we published our results demonstrating increased AMPAR surface expression in the NAc of sensitized rats on WD21 (Boudreau and Wolf, 2005), they appeared to conflict with a prior study demonstrating a decreased AMPA/NMDA ratio in the NAc shell of cocaine-sensitized mice on WD10–14 (Thomas et al., 2001). The decreased AMPA/NMDA ratio was attributable, at least in part, to decreased AMPAR number or function; altered NMDAR function was not detected (Thomas et al., 2001). The results of Thomas

Sensitization

Many forms of LTP are produced by the addition of AMPAR to excitatory synapses, so the increased synaptic AMPAR levels observed in the NAc after withdrawal from repeated cocaine exposure might make it more difficult to produce further LTP. Unfortunately, no studies have addressed this possibility at the withdrawal times (7–21 days) associated with cocaine-induced increases in NAc AMPAR levels. Two studies examined earlier withdrawal times. Yao et al. (2004) found an enhanced magnitude of LTP at

Cocaine and amphetamine produce different effects on AMPAR transmission

Cocaine and amphetamine exhibit cross-sensitization in locomotor activity experiments and prior exposure to one drug enhances self-administration of the other (Kalivas and Weber, 1988, Pierce and Kalivas, 1995, Bonate et al., 1997, Ferrario and Robinson, 2007, Liu et al., 2007). Might common AMPAR adaptations be responsible for these observations? While this is a tempting hypothesis, it is clear that amphetamine and cocaine have different effects on NAc AMPAR. This is evident from results

Future directions

This review focused very narrowly on the effects of cocaine on AMPAR in MSN of the NAc because the field has developed to the point where a detailed and critical review seemed warranted. However, it is important to note that we did not comprehensively address several critical issues related to this topic, including: (1) heterogeneity of NAc neurons, defined anatomically, functionally, and pharmacologically, (2) different responsiveness of NAc MSN in the upstate and the downstate, (3)

Acknowledgements

Our own work was supported by DA009621, DA015835 and DA000453 to M.E.W. and postdoctoral National Research Service Award DA024502 to C.R.F. We thank members of the Wolf laboratory (especially Amy C. Boudreau, Kelly L. Conrad, Christopher L. Nelson, Jeremy M. Reimers, and Xiu Sun) for their role in the development of ideas discussed in this review. We also thank Dr. Michela Marinelli for helpful editorial comments.

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