Sex Differences in Cannabinoid Dependence and Analgesia

描述(由申请人提供)：流行病学研究表明，女性和男性的药物滥用和依赖模式不同。D9-四氢大麻酚(THC)是大麻的主要精神活性替代品，已有报道在人类和啮齿动物模型中存在性别差异；然而，导致这些差异的机制尚不清楚，这是拟议的研究重点。目标1和目标2将分别确定THC的抗伤害效应和依赖相关效应中的性别差异是否受性激素、雌二醇和孕酮以及男性睾酮的调节。重点将放在重复服用THC对行为的影响上，因为根据定义，药物滥用需要长期使用。与依赖相关的行为包括快速戒断(躯体和情感体征)、辨别(大麻中毒的啮齿动物模型)和条件性位置偏好/厌恶(CPP/CPA)，这是一种评估药物效应与愉悦或厌恶相关程度的啮齿动物模型。还将评估性别差异对THC的抗伤害感受作用的耐受性，THC是大麻类药物的潜在治疗适应症之一。目的3将描述THC的药代动力学，并将确定中枢CB1和CB2受体密度以及与行为变化相关的功能和内源性大麻素水平的区域性变化。了解大麻素的抗伤害作用和依赖相关效应的性别差异的基本机制，将有助于开发针对性别的方法来治疗大麻依赖，并在治疗方面使用大麻类药物，特别是在治疗疼痛和痉挛方面。此外，增加对影响内源性大麻素系统功能的内分泌机制的科学知识可以加强对各种疾病的了解和治疗，这些疾病涉及内源性大麻素系统的失调，包括药物滥用、精神障碍、肥胖和各种神经疾病。

DESCRIPTION (provided by applicant): Epidemiological studies have shown that women and men differ in their patterns of substance abuse and dependence. Sex differences in the effects of D9-tetrahydrocannabinol (THC), the primary psychoactive substituent of marijuana, have been reported in humans and in rodent models; however, the mechanisms responsible for these differences are unclear and are the focus of the proposed research. Aims 1 and 2 will determine whether sex differences in the antinociceptive and dependence-related effects of THC, respectively, are modulated by gonadal hormones, estradiol, and progesterone in females and testosterone in males. Emphasis will be on the effects of repeated THC administration on behavior, as substance abuse, by definition, requires chronic use. Dependence-related behaviors include precipitated withdrawal (somatic and affective signs), THC discrimination (a rodent model of marijuana intoxication), and conditioned place preference/aversion (CPP/CPA), a rodent model to assess the degree to which drug effects are associated with pleasure or aversion. Sex differences in tolerance to the antinociceptive effects of THC, one of the potential therapeutic indications of cannabinoid-based medications, will also be evaluated. Aim 3 will characterize the pharmacokinetics of THC and will identify regional alterations in central CB1 and CB2 receptor densities and functioning and endocannabinoid levels that are associated with behavioral changes. Understanding these basic mechanisms underlying sex differences in antinociceptive and dependence-related effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically, specifically in the treatment of pain and spasticity. In addition, increasing scientific knowledge of endocrinological mechanisms that affect endocannabinoid system functioning could enhance understanding and treatment of a wide variety of disorders, in which dysregulation of the endocannabinoid system has been implicated, including substance abuse, psychiatric disorders, obesity, and various neurological disorders.