Behavioral and pharmacological determinants of cannabinoid reinforcement and effects on cognition in rhesus monkeys

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 DESCRIPTION (provided by applicant): Marijuana is the most commonly abused illicit substance in the United States; however, much information is needed regarding the long-term consequences of marijuana abuse. The difficulty in demonstrating the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana, by the self-administration (SA) procedure in animal models remains an impediment to developing treatments for human marijuana abuse. Successful efforts have been limited to one laboratory using squirrel monkeys and experimental parameters that have not been previously employed. Every other THC SA attempt to date using nonhuman primate (NHP) species (rhesus monkeys) or rodents has been unsuccessful. The extension of the THC SA model to include rhesus monkeys is important because this species is more phylogenetically similar to humans than any other currently available preclinical laboratory species, e.g., mice, rats, squirrel monkeys, which would enhance the ability to accurately generalize results to human drug abuse. Thus, the major goal of this application is to establish the experimental conditions necessary for THC SA to be maintained in rhesus monkeys by first utilizing conditions that promoted THC SA in squirrel monkeys, including schedule of reinforcement and a broader range of doses (Specific Aim 1). Another goal of this Aim is to characterize the individual differences that underlie qualitative an quantitative differences in THC SA in order to determine critical variables that could be modified to optimize the procedure. Preliminary data with the synthetic cannabinoid agonist CP 55,940 demonstrated an inverse relationship between sensitivity to the rate- decreasing effects and reinforcing effects. Therefore, Specific Aim 2 will determine if tolerance to the rate- decreasing effects of THC will enhance the reinforcing effects of THC. Such an outcome would suggest that preclinical models require a period of repeated drug treatment before assessing THC SA. Furthermore, disruptions in cognitive function are a major consequence of drug abuse and a factor that may affect treatment outcome. Although the acute effects of THC on cognitive function have been well characterized, the residual effects (i.e., after the intoxicating effects have subsided) and long-term effects (i.e., several weeks of abstinence and beyond) are equivocal. Thus, studies in Specific Aim 3 will determine the residual effects (22 hrs after administration) of chronic THC and changes during abstinence on multiple cognitive domains using a within-subjects design in rhesus monkeys. Overall, these studies will provide valuable insight on the nature, persistence, and reversibility of cannabis-related cognitive deficits associated with long-term use that clinicians can use to maximize treatment retention and success rate.