Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self‐administration in rats

Abstract

Cocaine self-administration is associated with a propensity to relapse in humans and reinstatement of drug seeking in rats after prolonged withdrawal periods. These behaviors are hypothesized to be mediated by molecular neuroadaptations within the mesolimbic dopamine system. However, in most studies of drug-induced neuroadaptations, cocaine was experimenter-delivered and molecular measurements were performed after short withdrawal periods. In the present study, rats were trained to self-administer intravenous cocaine or oral sucrose (a control non-drug reward) for 10 days (6-h/day) and were killed following 1, 30, or 90 days of reward withdrawal. Tissues from the accumbens and ventral tegmental area (VTA) were assayed for candidate molecular neuroadaptations, including enzyme activities of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin-dependent kinase 5 (cdk5), tyrosine hydroxylase (TH) and glutamate receptor subunits (GluR1, GluR2 and NMDAR1). In the accumbens of cocaine-trained rats, GluR1 and NMDAR1 levels were increased on days 1 and 90, while GluR2 levels were increased on days 1 and 30, but not day 90; PKA activity levels were increased on days 1 and 30, but not day 90, while AC activity, TH and cdk5 levels were unaltered. In the VTA of cocaine-trained rats, NMDAR1 levels were increased for up to 90 days, while GluR2 levels were increased only on day 1; TH and Cdk5 levels were increased only on day 1, while PKA and AC activity levels were unaltered. Cocaine self-administration produces long-lasting molecular neuroadaptations in the VTA and accumbens that may underlie cocaine relapse during periods of abstinence.

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…For example, the previous report of Gria2 induction in the mPFC used noncontingent administration (Ghasemzadeh et al, 1999) and previous reports clearly indicate that contingency affects the gene expression response (Mutschler et al, 2000). The most similar previous report of expression changes with long-term abstinence following cocaine self-administration (Lu et al, 2003) examined protein expression levels. While we have previously found close correlations between cocaine-responsive mRNA and protein expression (Freeman et al, 2001b), we have also described changes in protein expression that are not always accompanied by mRNA expression changes, depending on the brain region (Bennett et al, 1999).…”

“…In cocaine selfadministering rats, increased responding on the previously active lever was evident after 7 or more days of cocaine abstinence (Grimm et al, 2001). This phenomenon is incubation, and further studies demonstrated that persis-tent changes in mesolimbic (Lu et al, 2003) and amygdalar (Lu et al, 2005a) protein expression accompanied the behavioral change. This work suggests that long-lasting behavioral changes in drug-seeking and the underlying neurobiological alterations can be modeled in rodents.…”

“…These reports are paralleled by rodent studies of relapse and reinstatement (for review, see Rebec and Sun, 2005;Kalivas and McFarland, 2003). At the molecular level, abstinence-induced or abstinence-persistent changes in mRNA and protein expression have been described in the mPFC and NAc after cocaine self-administration (Lu et al, 2003;Sutton et al, 2003). Other brain structures, eg amygdala (Lu et al, 2007(Lu et al, , 2005b and ventral subiculum (Vorel et al, 2001;Taepavarapruk and Phillips, 2003), also play roles in reinstatement and will need to be examined in future studies.…”

Previous Exposure to Psychostimulants Enhances the Reinstatement of Cocaine Seeking by Nucleus Accumbens AMPA

“…Effect of psychhostimulants on cocaine self-administration N Suto et al protein levels in the NAcc, leaving GluR3 and GluR4 protein levels unchanged (Lu et al, 1997;Lu and Wolf, 1999). On the other hand, exposure to cocaine 17-90 days earlier has been reported to either slightly increase GluR1 (Churchill et al, 1999;Scheggi et al, 2002;Lu et al, 2003) and GluR2 protein levels, leave GluR1 (Fitzgerald et al, 1996;Ghasemzadeh et al, 1999) and GluR2 (Fitzgerald et al, 1996;Churchill et al, 1999;Ghasemzadeh et al, 1999;Scheggi et al, 2002) protein and mRNA levels unchanged and decrease GluR3 and GluR4 mRNA levels (Ghasemzadeh et al, 1999). In another study, GluR1 and GluR2/3 protein levels were not increased 1 week following cocaine self-administration unless animals were subjected to an extinction procedure during the withdrawal period (Sutton et al, 2003).…”

Self-administration of cannabinoids by experimental animals and human marijuana smokers

“…One must consider, however, that the functional state of brain reward circuits in drug naïve subjects versus experienced subjects that have chronically self-administered a training drug such as cocaine is likely different, as recently demonstrated by findings that dopamine elevations in the nucleus accumbens produced by cocaine are dramatically higher in experienced subjects compare to naïve subjects (Duvauchelle et al, 2000;Zapata et al, 2003). Neurobiological adaptations that occur over time in subjects that have repeatedly self-administered psychoactive drugs (e.g., Stefanski et al, 1999;Lu et al, 2003;Stefanski et al, 2004;Thompson et al, 2004) might predispose them to self-administer a test drug or limit the self-administration of a test drug Nader and Mach, 1996;Wojnicki and Glowa, 1996;Tella et al, 1996;Morgan et al, 2002). Thus, it can be important to study the acquisition of drug selfadministration behavior in drug naïve subjects (e.g., Deneau and Seevers, 1964).…”