Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving

Abstract

Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

Synaptic AMPA receptor composition in development, plasticity and disease

“…As with fear extinction, this is reversed by mGluR1 activation, suggesting mGluR1-dependent LTD may represent a general mechanism to reverse CP-AMPAR upregulation 157 . Similarly, CP-AMPARs increase in the nucleus accumbens (NAc) in rats during cocaine withdrawal and their blockade reduces cue-induced cocaine seeking, consistent with roles in addiction 159 . Thus, there is strong evidence that CP-AMPARs play a critical role in in vivo.…”

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

“…Thus, the second conclusion of our study is that it may be difficult to selectively affect cocaine memories by targeting the UPS, although further studies are necessary to explore this. Recruitment of similar synaptic mechanisms upon retrieval of cocaine and saline memories makes sense if retrieval is only the first step in enabling a memory to engage the NAc mechanisms that convert 'motivation to action' (Mogenson et al, 1980) and suggests that cocaine-specific adaptations affecting steps downstream of retrieval (eg, strengthening of AMPA receptor transmission; Conrad et al, 2008;Loweth et al, 2014) explain the stronger behavioral response to cocaine-paired cues after prolonged withdrawal.…”

“…First, we measured basal UPS activity after a period of withdrawal (WD50-60) when craving has incubated and stabilized at high levels (Lu et al, 2004). The NAc was studied because neuroadaptations in this region are required for expression of incubation after prolonged withdrawal (Conrad et al, 2008;Loweth et al, 2014). Importantly, these neuroadaptations are very stable from WD30-70, further justifying our selection of the WD50-60 period (Wolf and Tseng, 2012), and can be detected under basal conditions (ie, they do not require a seeking test to be evident).…”

“…After 5-7 days of recovery, selfadministration training was conducted on 10 consecutive days (6 h/day) in operant chambers equipped with two nosepoke holes. Responding in one hole (active) resulted in intravenous infusion of cocaine (0.5 mg/kg/infusion in a 100 μl/kg volume over 3 s) or saline (32 μl/infusion) on an FR1 schedule, paired with illumination of a cue light (for detailed descriptions, see Conrad et al, 2008;Loweth et al, 2014). Responding in the inactive hole had no consequences.…”

“…We compared UPS activation at early and late withdrawal times, when craving is low and high, respectively, in order to assess its relationship both to the age of the memory and the intensity of craving. We focused on the nucleus accumbens (NAc) because the expression of 'incubated' craving depends upon synaptic plasticity in this region (Conrad et al, 2008;Loweth et al, 2014). We also studied other regions-amygdala, prefrontal cortex (PFC) and dorsolateral striatum (DLS) -implicated in cue-induced cocaine seeking after withdrawal (Grimm et al, 2003;Fuchs et al, 2006;Lu et al, 2005aLu et al, , b, 2007See et al, 2007;Koya et al, 2009;Pacchioni et al, 2011;Lee et al, 2013;Ma et al, 2014;Pascoli et al, 2014).…”