L-type calcium channel blockade attenuates the anxiogenic-like effects of cocaine abstinence in female and male rats.

Cocaine abstinence and withdrawal are linked to relapse and heightened anxiety. While L-type calcium channels (LTCCs) have been associated with cocaine use disorders in humans and drug-seeking in rodents, their role in mood-related symptoms during cocaine abstinence remains unclear. We addressed this by investigating the ability of LTCC blockade with isradipine to alter the mood-related behavioral phenotypes induced by cocaine abstinence. Female and male Sprague-Dawley rats were trained to self-administer cocaine or saline, followed by a 14-day period of abstinence. Subsequently, behavioral responses were examined using the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). Cocaine-abstinent rats showed decreased open arm time in the EPM and increased immobility time in the FST with no changes in the SPT. Isradipine (0.4 mg/kg or 1.2 mg/kg, i.p.), reversed the anxiogenic-like EPM behavior in female cocaine-abstinent rats, whereas only the higher dose (1.2 mg/kg, i.p.) was effective in male cocaine-abstinent rats. In the FST, the lower dose (0.4 mg/kg, i.p.) of isradipine reversed the increased immobility time observed in cocaine-abstinent female and male rats, with no isradipine effect in saline-abstinent rats. In contrast 1.2 mg/kg, i.p. isradipine decreased immobility time in both cocaine and saline abstinent female and male rats. In summary, isradipine administration reversed the anxiogenic and increased the FST immobility time associated with cocaine abstinence in a dose and sex-dependent manner. The data underscore the importance of further investigation of LTCC mechanisms and their therapeutic potential for mood disorders associated with cocaine use disorder.