Investigating the Impact of Nicotine and Alcohol Co-Use on the Abuse Potential of Cocaine In Monkey Models

Cocaine use disorder (CUD) continues to be a major public health problem worldwide, with no FDA-approved treatments. An important consideration in evaluating neural and behavioral mechanisms of CUD and potential treatment strategies is the observation that most individuals suffering from CUD also co-use other substances, including tobacco products and alcohol. The goal of this new research project is to extend the study of cocaine misuse to include the co-use of nicotine and/or alcohol in female and male cynomolgus monkeys. When alcohol and cocaine are co-used, there is an active metabolite formed, cocaethylene, which we recently showed had reinforcing effects that were similar in potency and reinforcing strength to cocaine, when studied under a progressive-ratio schedule of reinforcement. Preliminary data using a cocaine vs. food choice paradigm, found that co-use of nicotine not only potentiated the reinforcing effects of cocaine, but it enhanced the reinforcing strength of cocaine. Studies proposed in this application will extend the evaluation of cocaine misuse to determine how nicotine and cocaethylene influence the ability of behavioral and pharmacological interventions to decrease the reinforcing effects of cocaine and pharmacological interventions on the discriminative stimulus effects of cocaine. In Aim 1, we propose to examine several behavioral interventions on drug self-administration. For these studies, monkeys will choose between cocaine (including saline) and food and the following interventions will be examined: delay discounting involving both food and drug (cocaine ± nicotine and cocaethylene ± nicotine) delays; changes in the magnitude of the food reinforcer; and negative punishment, using response-contingent timeouts. The studies in Aim 2 will examine the effects of chronic drug treatments in female and male monkeys self-administering cocaine ± nicotine and cocaethylene ± nicotine in the context of an alternative, non-drug, reinforcer (food-drug choice). We will combine chronic pharmacological treatments with behavioral interventions in an effort to further decrease cocaine choice. The goals of Aim 3 are to examine how nicotine and cocaethylene influence the discriminative stimulus effects of cocaine. Pharmacological treatments examined on self-administration, will also be examined in this model of subjective drug effects. The scientific premise for these studies is that co-use of nicotine and alcohol with cocaine result in different behavioral consequences compared with cocaine alone and are not simply additive drug effects. Thus, co-use of alcohol and/or nicotine with cocaine will require different behavioral and pharmacological treatment strategies than cocaine alone. Results from these studies will aid in the development of personalized medicine strategies for cocaine use disorder that incorporates polysubstance use.