Sex Differences in Cannabinoid Dependence and Analgesia

描述（由申请人提供）：酗酒是一个日益严重的问题，在世界范围内。年轻人（16-24岁）特别容易受到酗酒的不良影响，酗酒通常与包括大麻在内的次级滥用药物一起消费。先前的研究表明，酒精可能与大麻素激动剂如大麻的主要精神活性替代品D9-四氢大麻酚（THC）共享药理作用。此外，以前的工作已经发现，这些影响可能是由酒精对内源性大麻素系统的影响来调节的。虽然大部分关于酒精和大麻素的临床前工作都是在雄性啮齿动物中进行的，但在雌性啮齿动物中进行的稀疏研究结果表明存在性别选择性差异，女性通常对乙醇和THC的药理作用表现出增强的敏感性。在父母补助金，我们的目标是描述THC的一些差异，并调查潜在的机制。在本补充中，我们建议将乙醇/大麻素共同滥用的检查纳入我们的整体研究策略。与母基金一样，将使用体内和体外综合措施。为了利用当地对酒精对肝脏影响的专业知识，我们扩大了父母补助金中存在的双重大脑和行为重点，以纳入对酒精和THC对肝脏影响的研究。在拟议的项目中，我们将研究酒精和THC联合给药的急性体内药理学作用的性别差异，以及重复间歇性联合给药后的奖励/厌恶效应（目的1）。这些行为效应将与大脑和肝脏中内源性大麻素系统功能的体外测量以及两种物质共同滥用引起的肝损伤程度的测定相关（目标2）。了解酒精和大麻共同滥用的性别选择性影响在这个时候特别重要，因为最近美国对大麻使用的法律的限制有所放松，这可能与男女酒精和大麻共同滥用率的增加有关。

DESCRIPTION (provided by applicant): Binge alcoholism is a growing problem worldwide. Young adults (16-24 years of age) are particularly prone to the adverse effects of alcoholic binging, which is often consumed with secondary drugs of abuse including marijuana. Previous research has suggested that alcohol may share pharmacological effects with cannabinoid agonists such as D9-tetrahydrocannabinol (THC), the primary psychoactive substituent of marijuana. Further, previous work has found that these effects may be modulated by alcohol's effects on the endocannabinoid system. Although much of the preclinical work on both alcohol and cannabinoids has been conducted in male rodents, results of sparse studies in female rodents have suggested sex-selective differences, with females often exhibiting enhanced sensitivity to the pharmacological effects of ethanol as well as THC. In the parent grant, our goals are to characterize some of these differences for THC and to investigate potential mechanisms. In this supplement, we propose to incorporate examination of ethanol/ cannabinoid co-abuse into our overall research strategy. As with the parent grant, integrated in vivo and in vitro measures will be used. To take advantage of local expertise on the hepatic effects of alcohol, we have expanded the dual brain and behavior focus present in the parent grant to incorporate research on the effects of alcohol and THC on the liver. In the proposed project, we will investigate sex differences in the acute in vivo pharmacological effects of alcoho and THC co-administration, as well as their rewarding / aversive effects following repeated intermittent co-administration (Aim 1). These behavioral effects will be correlated with in vitro measures of endocannabinoid system functioning in the brain and the liver and with determination of the extent of liver injury induced by co-abuse of both substances (Aim 2). Understanding the sex-selective effects of co-abuse of alcohol and marijuana is particularly critical at this time since the recent loosening of legal restrictions on marijuana use in the U.S. will likely be associated with increased rates of alcohol-marijuana co-abuse in both sexes.