Drug Self Administration and Withdrawal Effects on Cognitive Function

描述(由申请人提供)：静脉注射(IV)非人类灵长类动物(NHP)的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(首席调查员)获得支持和“保护时间”，以获得进行NHP自治研究的培训和经验。这次培训将推进他的科学职业目标，并解决对在这一方法方面经验丰富的新的年轻调查人员的需求。首席调查员将应用他新开发的专业知识来研究两种高度依赖和滥用倾向的自我给药(大麻有效成分四氢大麻酚[9-THC]、羟考酮和处方阿片类止痛剂)对认知的不同方面的潜在不良影响。在这个项目中，首席调查员首先将在McLean医院/哈佛医学院在J.Bergman博士的指导下完成IV自我管理方法的强化培训计划，J.Bergman博士因其在NHP的IV自我管理工作而受到国际认可。这项培训将包括自我管理方法的概念和实践方面。首席调查员将熟练掌握长时间(如2-3年)植入和维护静脉导管所需的外科/技术技能。此外，在日常持续研究羟考酮的强化作用期间进行的培训将使您熟悉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。第二，首席调查员将接受大麻素自我管理方面的高级培训，以学习促进以下药物研究的技术和行为技能 在实验动物中不太容易被确定为增强剂。培训将在S.R.Goldberg博士在NIDA/IRP实验室的共同指导下进行，他在过去12年里在那里开创、复制和扩大了这些努力。第三，首席调查员将通过检查持续自我给药的羟考酮和9-THC在新的学习和记忆测试中的影响，来研究它们对认知相关行为的影响。羟考酮和9-THC都会产生身体依赖和成瘾，并引起重大的公共卫生问题。羟考酮是一种比9-THC更强健的增强剂，但对认知的影响可能较小；因此，研究这两种增强剂所获得的经验将是首席调查员培训的一个重要特点。在羟考酮和9-THC维持的受试者中，分别使用拮抗剂的纳曲酮和利莫那班进行治疗后，以及在他们停止静脉注射自我给药不同的禁欲时期后，也将评估基于认知的表现的变化。这些研究将提供有关认知障碍的信息，这些障碍可能伴随着这些药物的自我给药。这一信息对于了解和最终消除药物成瘾治疗中的这种影响至关重要。总体而言，该项目将为首席调查员提供独特的专业知识和视角，以便继续研究吸毒成瘾对认知的影响。

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.