Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration

Abstract

BackgroundMany studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability.ResultsWhole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; ± 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.ConclusionsTogether, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

“…In vitro studies demonstrate that BRG1 is involved in the organization of actin filaments (48–50). Similarly, BRG1 binding was increased on genes involved in synaptic and morphological adaptation, including drebrin (51, 52) and adenylyl cyclase-associated protein 2 (53, 54). The binding of BRG1 to the promoter regions of these genes may in turn alter the synaptic plasticity in NAc medium spiny neurons, and thus regulate the behavioral response to cocaine (8, 55).…”

Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice

“…Together, this suggests that lasting neuroadaptive changes in the mPFC underpin continued cocaine seeking during abstinence. Moreover, the enduring contribution of the mPFC to drug-seeking behaviour is echoed in steadfast transcriptional and proteomic changes that persist for up to 100 days of forced abstinence following cocaine self-administration (Freeman et al, 2010, Freeman et al, 2008, Lull et al 2009). Finally, at the cellular level, the neuronal genome could represent a more suitable repository for persistent acquired epigenetic modifications, as mature neurons are not subject to cell division (Griffith & Mahler, 1969).…”

Functional consequences of cocaine re-exposure after discontinuation of cocaine availability

“…Specifically, some investigations of affect, craving levels, and the cognitive abilities of addicts have shown that there is some evidence for improvement after drug use has terminated (Coffey et al 2000; Weddington et al 1990; Satel et al 1991), although other studies have provided support for continuing deficits (Herning et al 1990; Berry et al 1993). Studies in animal models are consistent with an absence of recovery (Shaham and Hope, 2005; Freeman et al 2008, 2010; Nestler, 2001; Nader et al 2006), as well as the development of new adaptations in, for example, the glutamate system (Baker et al 2003; Conrad et al 2008). There are, however, also reports of the moderation or amelioration of neurobiological adaptations that have accompanied cocaine exposure (Nader et al 2006; Beveridge et al 2009; Freeman et al 2010).…”

“…Studies in animal models are consistent with an absence of recovery (Shaham and Hope, 2005; Freeman et al 2008, 2010; Nestler, 2001; Nader et al 2006), as well as the development of new adaptations in, for example, the glutamate system (Baker et al 2003; Conrad et al 2008). There are, however, also reports of the moderation or amelioration of neurobiological adaptations that have accompanied cocaine exposure (Nader et al 2006; Beveridge et al 2009; Freeman et al 2010). Taken together, these data suggest a complex interaction of numerous new and enduring adaptations in multiple brain systems accompanying discontinuation of drug use.…”