Endocrine and gene expression changes following forced swim stress exposure during cocaine abstinence in mice

Abstract

Stress can reinstate previous cocaine-seeking long after drug is no longer present. However, little is known regarding the effect of chronic drug exposure and subsequent drug abstinence on responsivity to stress. To determine the effect of acute (24-h) and prolonged (14-day) drug-free periods in cocaine-experienced mice on behavioral, endocrine, and molecular outputs following stress exposure. Mice were administered a cocaine binge (15 mg/kg, every hour for 3h) for 2 weeks. Following a 24-h or 14-day drug-free period, stress responsivity, along with levels of anxiety, were measured using the forced swim test and elevated zero maze, respectively. In addition, alterations in the levels of plasma corticosterone, corticotrophin-releasing factor (CRF) mRNA, brain-derived neurotrophic factor (BDNF) mRNA, and histone acetylation at their respective promoters were examined following stress exposure. At both acute and prolonged abstinence time points, behavioral measures were essentially unaltered; however, cocaine-experienced mice exhibited an augmented corticosterone response to the forced swim stress compared to saline-treated mice. Stress exposure increased BDNF mRNA levels in the ventral tegmental area (VTA) and nucleus accumbens (NAc) only in cocaine-experienced mice following a prolonged, but not acute, drug-free period. Increased BDNF mRNA in the NAc was associated with an increase in acetylated histone 3 (AcH3) at the BDNF I promoter. CRF mRNA levels were increased in the amygdala (AMYG); however, this was not associated with alterations in histone acetylation at the promoter. These results demonstrate that drug history and prolonged abstinence can alter the endocrine and molecular responses to stress, which may facilitate the reinstatement of drug-seeking behaviors.