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

 描述(申请人提供)：大麻是美国最常见的被滥用的非法物质；然而，关于滥用大麻的长期后果，需要大量的信息。Δ-9-四氢大麻酚(THC)是大麻的主要精神活性成分，在动物模型中难以通过自我给药(SA)程序证明其增强作用，这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，使用松鼠猴子和以前没有使用过的实验参数。到目前为止，所有其他使用非人类灵长类(NHP)物种(恒河猴)或啮齿动物的THC SA尝试都没有成功。将THC SA模型扩展到包括恒河猴是很重要的，因为与目前可用的任何其他临床前实验室物种相比，这个物种在系统发育上更接近人类，例如小鼠、大鼠、松鼠猴子，这些物种 将提高准确概括人类药物滥用结果的能力。因此，本申请的主要目的是通过首先利用在松鼠猴中促进THC SA的条件，包括加强时间表和更广泛的剂量范围(特定目标1)，来建立在恒河猴中维持THC SA所需的实验条件。这一目标的另一个目标是表征构成THC SA定性和定量差异的个体差异，以便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的初步数据表明，对减速效应和增强效应的敏感性之间存在相反的关系。因此，特定的目标2将决定对THC减速效应的耐受性是否会增强THC的增强作用。这样的结果将表明，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，认知功能障碍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描述，但其残留影响(即在醉酒效应消退后)和长期影响(即几个星期的戒断及以后)是模棱两可的。因此，特定目标3的研究将采用受试者内设计在恒河猴身上确定慢性THC的残余效应(给药后22小时)和戒断期间对多个认知域的变化。总体而言，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缺陷来最大限度地保持治疗和提高成功率。

 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.