Intravenous (IV) drug self-administration procedures in nonhuman primates (NHP) provide powerful laboratory tools with which to study persistent drug taking behavior and its neurobehavioral consequences. The present K01 application is designed to obtain support and protected time for Dr. Brian Kangas (Principal Investigator) to gain training and experience in conducting NHP self-administration studies. This training will advance his scientific career goals and also address the need for new young investigators experienced in this methodology. The Principal Investigator will apply his newly-developed expertise to examine the potentially adverse effects of two self-administered drugs that have high dependence and abuse liability (tetrahydrocannabinol [9-THC], the active ingredient in marijuana, and oxycodone, and the prescription opioid analgesic) on different aspects of cognition. In this project, the Principal Investigator first will complete an intensive training program in IV self-administration methodology at McLean Hospital/Harvard Medical School under the mentorship of Dr. J. Bergman, who is internationally recognized for his IV self-administration work in NHP. This training will include conceptual and practical aspects of self- administration methodology. The Principal Investigator will become skilled in the surgical/technical skills needed to implant and maintain IV catheters over long periods of time (e.g., 2-3 years). In addition, training during daily ongoing studies of oxycodone's reinforcing effects will provide familiarity with technical, behavioral, and tactical issues that arise during V self-administration studies, and decision-making strategies to efficiently achieve research goals. Second, the Principal Investigator will receive advanced training in cannabinoid self-administration to learn the technical and behavioral skills that facilitate studies with drugs that are less readily established as reinforcers in laboratory animals. This training will occur under Dr. S.R. Goldberg's co-mentorship in his laboratory at NIDA/IRP, where he has pioneered, replicated, and expanded these efforts over the last 12 years. Third, the Principal Investigator will conduct studies of the effects of persistently self-administered oxycodone and 9-THC on cognition-related behavior by examining their impact in novel assays of learning and memory. Both oxycodone and 9-THC produce physical dependence and addiction, and present major public health concerns. Oxycodone is a more robust reinforcer than 9-THC but may have lesser effects on cognition; thus, the experience gained by studying both types of reinforcers will be an important feature of the Principal Investigator's training. Changes in cognitive-based performance also will be evaluated following treatment with the antagonist's naltrexone and rimonabant in, respectively, oxycodone- and 9-THC -maintained subjects and, as well, following the discontinuation of their IV self-administration for varying periods of abstinence. These studies will provide information on cognitive impairments that may attend self-administration of these drugs. This information is essential for understanding and eventually countering such effects in the treatment of drug addiction. Overall, this project will provide the Principal Investigator with a unique expertise and perspective for continuing research on the cognitive impact of drug addiction.
This project will provide protected time for Dr. Kangas to: 1) obtain the expertise necessary for sophisticated and multidimensional IV self-administration research in nonhuman primates, and 2) as a first exercise of this new expertise, conduct studies to determine how self-administration of two widely abused and addictive drugs, THC and oxycodone, alters cognitive abilities. Despite their common abuse, little is known regarding the cognition-related effects of THC or oxycodone when self-administered during long periods of time. Studies with each drug are designed to assess the effects of long-term IV self-administration and withdrawal on learning and memory, which is essential for understanding and eventually countering adverse effects of opioid or cannabis addiction on different aspects of cognitive function.
