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

 描述（由申请人提供）：大麻是美国最常滥用的非法物质;然而，关于大麻滥用的长期后果需要大量信息。在动物模型中通过自我给药（SA）程序证明Δ9-四氢大麻酚（THC）（大麻的主要精神活性成分）的增强作用的困难仍然是开发人类大麻滥用治疗方法的障碍。成功的努力仅限于一个实验室使用松鼠猴和实验参数，以前没有采用。迄今为止，使用非人类灵长类（NHP）物种（恒河猴）或啮齿动物的所有其他THC SA尝试都没有成功。将THC SA模型扩展到包括恒河猴是重要的，因为该物种比任何其他目前可用的临床前实验室物种（例如，老鼠，大白鼠，松鼠猴， 将增强准确地将结果推广到人类药物滥用的能力。因此，本申请的主要目标是通过首先利用在松鼠猴中促进THC SA的条件，包括强化时间表和更广泛的剂量范围，建立在恒河猴中维持THC SA所需的实验条件（具体目标1）。该目标的另一个目标是表征THC SA中定性和定量差异的个体差异，以确定可以修改以优化程序的关键变量。合成大麻素激动剂CP 55，940的初步数据证明了对速率降低效应和增强效应的敏感性之间的反比关系。因此，具体目标2将确定对THC的速率降低效应的耐受性是否会增强THC的增强效应。这样的结果表明，临床前模型在评估THC SA之前需要一段时间的重复药物治疗。此外，认知功能中断是药物滥用的一个主要后果，也是可能影响治疗结果的一个因素。虽然THC对认知功能的急性影响已经得到了很好的表征，但残余影响（即，在中毒作用消退之后）和长期作用（即，几个星期的禁欲和超越）是模棱两可的。因此，具体目标3中的研究将使用恒河猴中的受试者内设计来确定慢性THC的残留效应（给药后22小时）和戒断期间对多个认知领域的变化。总的来说，这些研究将为长期使用大麻相关认知缺陷的性质、持久性和可逆性提供有价值的见解，临床医生可以利用这些见解来最大限度地提高治疗保留率和成功率。

 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.