Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving

Highlights

• Incubation of cocaine craving is relevant to cue-induced relapse in abstinent users.

• CP-AMPARs in the NAc mediate expression of incubation after prolonged withdrawal.

• Decreased mGluR1 negative regulatory tone may promote CP-AMPAR accumulation.

• CP-AMPAR synaptic insertion may be enhanced by increased GluA1 phosphorylation.

• NAc BDNF does not mediate incubation but may contribute to its maintenance.

Abstract

Cue-induced cocaine craving in rodents intensifies or “incubates” during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (∼3–4 weeks) accumulation of Ca²⁺-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence.

This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.

Introduction

One of the major challenges in treating cocaine addiction is the propensity for abstinent users to relapse upon re-exposure to drug-associated cues (Hunt et al., 1971; Mendelson and Mello, 1996; Reichel and Bevins, 2009). It has been hypothesized that this may be because craving elicited by drug-related cues increases after acute abstinence and persists even after periods of prolonged abstinence (Gawin and Kleber, 1986). A similar phenomena referred to as "incubation" of cue-induced craving has been identified and extensively characterized in animals with a history of cocaine self-administration (e.g., Lu et al., 2004a; Pickens et al., 2011). These studies found that, in rats that underwent long access cocaine self-administration, context- and cue-induced cocaine seeking progressively increased (incubated) during withdrawal, peaking after about 1 month, persisting at similarly elevated levels at the 3 month time-point, and remaining elevated compared to withdrawal day (WD) 1 for at least 6 months (Grimm et al., 2001, 2003; Lu et al., 2004a, Lu et al., 2004b). Incubation of cue-induced craving has also been shown to occur in animals with a history of self-administering other drugs, including heroin, methamphetamine, and nicotine (see Pickens et al., 2011 for an extensive review), and has recently been shown to occur in abstinent human smokers (Bedi et al., 2011).

Alterations in neuronal activity and signaling pathways in the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), amygdala, and nucleus accumbens (NAc) have been linked to various aspects of incubated cocaine craving (Pickens et al., 2011). For instance, activity of the glial cell line-derived neurotrophic factor (GDNF) in the VTA plays a role in the development of incubation (Lu et al., 2009). Neuronal activity in the ventral mPFC (Koya et al., 2009) and the central nucleus of the amygdala (CeA) (Lu et al., 2005a, 2007) is important for the expression of incubated cocaine craving. Finally, as will be discussed in more detail (Section 5), incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) levels in the VTA, NAc and amygdala (Grimm et al., 2003).

This review will focus on adaptations in the NAc that contribute to incubated cocaine craving. We will begin by describing a key adaptation, the withdrawal-dependent accumulation of Ca²⁺-permeable AMPARs (CP-AMPARs), that mediates the expression of incubation after prolonged withdrawal. Then we will discuss specific mechanisms that are candidates for regulating this AMPAR plasticity, namely mGluR1 mediated synaptic depression, phosphorylation of GluA1 at the protein kinase A (PKA) site, and BDNF transmission in the NAc. For a more comprehensive review that covers incubation-related neuroadaptations in multiple brain regions, please see Pickens et al. (2011).