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，女性和男性在药物滥用和依赖模式上存在差异。大麻的主要精神活性取代物d9 -四氢大麻酚（THC）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，也是本研究的重点。目的1和目的2将确定四氢大麻酚的抗痛觉性和依赖性作用的性别差异是否分别受到性激素、雌二醇和黄体酮（女性）和睾酮（男性）的调节。重点将放在反复使用四氢大麻酚对行为的影响上，因为根据定义，药物滥用需要长期使用。依赖相关行为包括沉淀戒断（躯体和情感症状）、THC歧视（大麻中毒的啮齿动物模型）和条件偏好/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。四氢大麻酚是大麻素类药物的潜在治疗指征之一，对四氢大麻酚抗痛觉作用耐受性的性别差异也将进行评估。目的3将描述四氢大麻酚的药代动力学特征，并将确定与行为改变相关的中枢CB1和CB2受体密度、功能和内源性大麻素水平的区域变化。了解大麻素在抗痛觉性和依赖相关作用中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，并在治疗中使用基于大麻素的药物，特别是在治疗疼痛和痉挛方面。此外，对影响内源性大麻素系统功能的内分泌机制的科学认识的增加，可以加强对各种疾病的理解和治疗，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.