Invited reviewAdaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving
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).
Section snippets
Ca2+-permeable AMPA receptors (CP-AMPARs) are incorporated into NAc synapses during incubation and mediate its expression after prolonged withdrawal
AMPARs are tetramers comprised of GluA1-4 subunits. Their properties are dramatically altered by the presence or absence of the GluA2 subunit. Receptors lacking this subunit are Ca2+-permeable, exhibit larger single channel conductance and faster kinetics than GluA2-containing AMPARs, and display inward rectification due to voltage-dependent block by intracellular polyamines. Interest in CP-AMPARs has intensified in recent years as a result of studies demonstrating their involvement in certain
Group I mGluRs are linked to cocaine addiction
The group I mGluRs (mGluR1 and mGluR5) are postsynaptic receptors that couple to the Gq-like class of G-proteins. They are important in modulating neurotransmission and plasticity through their linkages with multiple signaling pathways as well as NMDA receptors (Lüscher and Huber, 2010). The NAc expresses mGluR1 and mGluR5 in similar abundance, mainly in extrasynaptic and perisynaptic regions (Testa et al., 1994; Mitrano and Smith, 2007; Mitrano et al., 2008, 2010). Interest in the role of
GluA1 phosphorylation sites
Phosphorylation of the GluA1 subunit is critical for regulating AMPAR channel function and trafficking during synaptic plasticity. GluA1 is phosphorylated on serine 845 by PKA, on serine 831 by Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase C (PKC), and on serine 818 by PKC (Boehm et al., 2006; Derkach et al., 2007; Shepherd and Huganir, 2007). The possible relevance of serine 845 and serine 831 for CP-AMPAR plasticity during incubation will be considered in Sections 4.2
BDNF regulates diverse types of plasticity, including CP-AMPAR plasticity
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, exerts its major biological functions through binding to tropomyosin receptor kinase B (TrkB). Activated receptors trigger a number of signal transduction cascades including the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3-K) and phospholipase C-γ (PLC-γ) pathways (Reichardt, 2006). Through these pathways, BDNF is an important mediator of diverse types of synaptic plasticity. It exerts both
Conclusions
CP-AMPARs accumulate in NAc synapses after ∼1 month of withdrawal from long access cocaine self-administration and mediate the expression of incubation of cue-induced cocaine craving (Conrad et al., 2008). While many questions remain about the neuroadaptations that underlie the delayed accumulation of CP-AMPARs, two mechanisms have been identified that are likely to play a significant role. First, mGluR1 exerts a negative regulatory effect on CP-AMPAR transmission that may decline in a
Acknowledgments
This work was supported by National Institutes of Health grants DA009621 (M.E.W. and K.Y.T.), DA0015835 (M.E.W.), Senior Scientist Research and Mentorship Award DA029099 (M.E.W.) and postdoctoral National Research Service Award F32 DA030844 (J.A.L.).
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