Sex Differences in Cannabinoid Dependence and Analgesia (parent grant)

描述（由申请人提供）：流行病学研究表明，妇女和男子在药物滥用和依赖模式方面存在差异。D9-四氢大麻酚（THC），大麻的主要精神活性取代物，在人类和啮齿动物模型中的作用存在性别差异;然而，造成这些差异的机制尚不清楚，这是拟议研究的重点。目的1和2将确定THC的抗伤害性和依赖性相关效应的性别差异是否分别受到性腺激素、雌二醇和孕酮（女性）和睾酮（男性）的调节。重点将放在重复THC管理对行为的影响上，因为根据定义，药物滥用需要长期使用。依赖性相关行为包括突然戒断（躯体和情感体征）、THC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），这是一种啮齿动物模型，用于评估药物效应与快乐或厌恶相关的程度。还将评估对THC的抗伤害效应的耐受性的性别差异，THC是基于大麻素的药物的潜在治疗适应症之一。目标3将描述THC的药代动力学特征，并确定与行为变化相关的中央CB 1和CB 2受体密度和功能以及内源性大麻素水平的区域变化。了解这些基本机制的性别差异的抗伤害性和依赖性相关的大麻素的影响，将有助于发展性别特异性的方法来治疗大麻依赖和使用大麻素为基础的药物治疗，特别是在治疗疼痛和痉挛。此外，增加影响内源性大麻素系统功能的内分泌机制的科学知识，可以加强对各种各样的疾病的理解和治疗，其中涉及内源性大麻素系统的失调，包括药物滥用，精神疾病，肥胖症和各种神经系统疾病。

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.