cAMP Response Element-Binding Protein Is Required for Stress But Not Cocaine-Induced Reinstatement

Abstract

Reinstatement of previously extinguished conditioned place preference (CPP) is precipitated by stress or drug exposure. Here, we show that acute exposure to forced swim stress (FS), in a context distinct from conditioning, induces reinstatement of cocaine CPP in wild-type mice. This behavior is accompanied by a pattern of phosphorylated cAMP response element-binding protein (pCREB) activation in discrete brain regions that is distinct from the pattern observed after cocaine-induced reinstatement. For example, previous cocaine conditioning increases pCREB levels in the amygdala, and acute exposure to FS, but not to cocaine, further augments these changes. In contrast, previous cocaine conditioning does not alter levels of pCREB in the nucleus accumbens, but acute exposure to FS increases pCREB levels in this region on reinstatement day. Furthermore, to determine whether these alterations of CREB are necessary in FS or cocaine-induced reinstatement, we examined the effect of these stimuli on reinstatement behavior in mice deficient in ␣ and ⌬ isoforms of CREB. The CREB ␣⌬ mutant mice show deficits in FS-induced reinstatement of conditioned place preference. In contrast, they show robust cocaine-induced reinstatement. This deficit in stress but not drug-induced reinstatement indicates a specific requirement for CREB in stress-induced behavioral responses to drugs of abuse.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…In contrast, both the footshock and forced swim were administered in a different apparatus and room in the reinstatement protocol described in the present study. This is consistent with recent reports from other research groups also showing that stress exposure outside the experimental chamber was able to reinstate drug seeking (Carey et al 2007;Kreibich andBlendy 2004, Ribeiro Do Cotuo et al 2006). Differences between reinstatement results obtained using operant self-administration protocols and place-conditioning protocols likely reflect the differences in the underlying learning mechanisms.…”

“…The ability of forced swim stress to induce reinstatement cocaine-seeking behavior has been reported after a 1-h (Carey et al 2007) and up to a 24-h delay (Kreibich and Blendy 2004). As with the present study, footshock stress has been shown to induce drug reinstatement when administered immediately (Erb et al 1996;.…”

“…Previous studies have used a conditioned place preference to study relapse of drug seeking (Kreibich and Blendy 2004;Mueller and Stewart 2000). The present study, however, differs in two aspects.…”

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn

“…Placing animals repeatedly into the apparatus with free access to all compartments for 30 min produced extinction, defined as a statistically significant decrease in the time spent in the cocaine-paired compartment during the extinction trial as compared to the immediate postconditioning response. As expected for the C57Bl/6J strain of mice, conditioned place preference responses subsided with repeated testing over the three week period (Szumlinski et al, 2002;Kreibich and Blendy, 2004;Brabant et al, 2005).…”

“…Place-conditioning began immediately following cocaine administration (10 mg/kg, s.c.), whereupon mice were consistently confined for 30 min in the appropriate outer compartment. A dose of 10 mg/kg s.c. cocaine was selected for this study as it has been shown previously to produce a reliable conditioned-place preference response in C57Bl/6J mice (Zhang et al, 2002;Kreibich and Blendy, 2004;Brabant et al, 2005). Conditioning with assay vehicle (0.9% saline, 0.3 ml/30 g body weight, s.c.) followed 4 h later in a similar manner, but paired to the opposite chamber.…”