Effects of cocaine self‐administration on cognition in monkeys and evaluation of cognitive enhancement as a therapeutic strategy

Abstract

Cocaine use is associated with impaired executive function, thus cognitive enhancement may aid relapse prevention. Four adult male rhesus monkeys with extensive cocaine self‐administration (SA) histories (> 5 year, >1.5 g/kg lifetime intake) and five age‐matched, cocaine‐naive monkeys were trained in morning sessions to perform cognitive tasks measuring learning, memory, response inhibition and behavioral flexibility; afternoon sessions consisted of cocaine SA (1.5 mg/kg/day) or food reinforcement (cocaine‐naive). Monkeys self‐administering cocaine in afternoon sessions showed impairments in reversal learning and set shifting in subsequent morning test sessions. FDG‐PET imaging showed lower glucose utilization in areas associated with error‐detection, memory, and reward compared to cocaine‐naive monkeys during set shifting, a measure of behavioral flexibility, demonstrating neurobiological and cognitive effects of cocaine. Working memory performance was disrupted on days following high dose cocaine SA. During periods of abstinence, nicotinic acetylcholine receptor (nAChR) stimulation via nicotine, the α4β2*‐ and α7‐subtype‐selective nAChR agonists varenicline and PNU‐282987 each improved working memory in cocaine‐experienced and cocaine‐naive monkeys, supporting nAChR stimulation for cognitive enhancement in cocaine‐dependent populations.