Drug Self Administration and Withdrawal Effects on Cognitive Function

描述（由申请人提供）：非人灵长类动物（NHP）的静脉（IV）药物自我给药程序为研究持续服药行为及其神经行为后果提供了强大的实验室工具。目前的K01申请旨在为Brian Kangas博士（首席研究员）获得支持和“保护时间”，以获得进行NHP自我管理研究的培训和经验。这次培训将促进他的科学职业目标，也解决了对这种方法有经验的新的年轻研究者的需求。首席研究员将运用其新开发的专业知识，研究两种高度依赖和滥用的自我给药药物（大麻中的活性成分四氢大麻酚[9-THC]和羟考酮，以及处方阿片类镇痛药）对认知不同方面的潜在不良影响。在这个项目中，首席研究员首先将在麦克林医院/哈佛医学院完成静脉注射自我给药方法的强化培训计划，导师是J. Bergman博士，他在NHP的静脉注射自我给药工作是国际公认的。该培训将包括自我管理方法的概念和实践方面。首席研究员将熟练掌握长时间（如2-3年）植入和维持静脉导管所需的外科/技术技能。此外，在日常进行的羟考酮强化效应研究中进行培训，将使患者熟悉V自我给药研究中出现的技术、行为和战术问题，以及有效实现研究目标的决策策略。其次，首席研究员将接受大麻素自我管理方面的高级培训，以学习促进药物研究的技术和行为技能

DESCRIPTION (provided by applicant): 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.