Cocaine self-administration in rhesus monkeys: Effects on neurobiology and cognition and evaluation of cognitive enhancement for addiction treatment.

摘要

No effective drug treatments for cocaine dependence exist, although combined behavioral and pharmacological interventions, reviewed in Chapter I, may lead to better treatment outcomes. The goal of the current research is to characterize neurobiological and cognitive deficits associated with cocaine use in monkeys, and examine cognitive enhancement as a pharmacotherapeutic approach to compliment behavioral methods.;Cocaine users show cognitive deficits in working memory (WM) and behavioral flexibility that persist into abstinence, although the extent and duration are not well established. In Chapter II, WM was assessed in rhesus monkeys with an ∼6 year cocaine self-administration (SA) history using a delay match-to-sample (DMS) task. High-dose cocaine SA in afternoon sessions resulted in impairments on WM in subsequent morning sessions; across 30 days of abstinence, DMS performance improved. In Chapter III, cocaine-experienced monkeys performed significantly worse and FDG-PET imaging showed lower neuronal activity in the anterior cingulate cortex, an area associated with error-detection, compared to cocaine-naive monkeys during set shifting, a measure of behavioral flexibility. In addition to effectively modeling cognitive deficits in monkeys, these data suggest pharmacological interventions may ameliorate deficits in neural function and cognition.;Nicotinic acetylcholine receptor (nAChR) agonists can stimulate dopamine function and enhance cognition. In Chapter IV, nAChR availability, assessed via [11C]-nicotine and PET was greater in the hippocampus in cocaine-experienced monkeys compared to controls, suggesting a target for further study. Acutely nicotine, a nonselective nAChR high-efficacy agonist, varenicline, a low-efficacy alpha4beta2* and PNU-282987, an alpha7 selective high-efficacy nAChR agonist improved WM in cocaine SA and control monkeys.;In Chapter V, chronic administration of varenicline increased the reinforcing strength of cocaine, while nicotine, varenicline and the nonselective antagonist mecamylamine potentiated the discriminative stimulus effects of cocaine. Thus, compounds that enhanced cognitive performance in monkeys with a cocaine SA history also increased the abuse liability of cocaine.;Integrating cognitive and behavioral pharmacology with PET imaging extends our knowledge of cocaine-related cognitive deficits, their neurobiological manifestations, and the utility of potential pharmacological adjuncts to behavioral treatments, providing a stronger assessment regarding therapeutic potential than any single method alone.