The role of the endogenous cannabinoid system in ethanol self-administration

描述（由申请人提供）：该项目的总体目标是探索乙醇自我给药升级和维持的神经生物学机制。目前的成瘾理论认为，长期的乙醇自我管理成为一种基于习惯的行为，而不是目标导向的行为。背外侧纹状体的神经可塑性被认为是习惯行为表达的必要条件，最近的研究表明内源性大麻素系统在习惯形成和纹状体可塑性的几种形式中都有作用。因此，该建议的主要假设是，维持长期的乙醇自我服用是一种基于习惯的行为，至少部分是由背外侧纹状体中的内源性大麻素信号介导的。这一假设将在本应用程序的两个具体目标中得到检验。第一个目的是通过体内微透析测量Long Evans大鼠背外侧纹状体中两种内源性大麻素anandamide和2-AG的细胞外水平，测量操作性乙醇自我给药对细胞外水平的影响。第二个目的是研究大麻素CB1受体在朗埃文斯大鼠习惯性操作乙醇自我给药表达中的参与。在建立乙醇自我给药后，将CB1受体拮抗剂利莫那班注入大鼠背外侧纹状体，以确定这些受体参与自我给药行为。总之，这些实验的结果应该增加对内源性大麻素系统在习惯性酒精自我给药中的作用的理解，并提供关于维持习惯性酒精自我给药机制的新信息。公共卫生相关性：本研究旨在探讨酒精成瘾行为发展和维持的神经生物学机制。从这项研究中获得的信息将有助于更好地理解慢性酒精使用过程中大脑的变化，并可用于开发更有效的酒精成瘾治疗方法。

DESCRIPTION (provided by applicant): The general objective of this project is to explore the neurobiological mechanisms responsible for the escalation and maintenance of ethanol self-administration. Current theories of addiction posit that long-term ethanol self-administration becomes a habit-based, rather that goal-oriented, behavior. Neuroplasticity in the dorsolateral striatum is thought to be necessary for the expression of habitual behavior, and recent research implicates the endocannabinoid system in both habit formation and in several forms of striatal plasticity. Thus, the overarching hypothesis of this proposal is that the maintenance of long-term ethanol self-administration is a habit-based behavior mediated, at least in part, by endocannabinoid signaling in the dorsolateral striatum. This hypothesis will be tested in the two specific aims of the present application. The first aim will measure the effect of operant ethanol self-administration by Long Evans rats on extracellular levels of the two endocannabinoids anandamide and 2-AG, as measured by in vivo microdialysis, in the dorsolateral striatum. The second aim will examine the involvement of the cannabinoid CB1 receptor during the expression of habitual operant ethanol self-administration in Long Evans rats. After establishing self- administration of ethanol, rats will receive infusions of the CB1 receptor antagonist rimonabant into the dorsolateral striatum to determine the involvement of these receptors in self-administration behavior. Together, the results of these experiments should increase the understanding of the role of the endocannabinoid system in habitual ethanol self-administration, and contribute new information regarding the mechanisms that underlie the maintenance of habitual self-administration of alcohol. Public health relevance: The present study aims to investigate neurobiological mechanisms underlying the development and maintenance of behaviors involved in alcohol addiction. The information gained from this research will lead to a better understanding the brain changes that occur as chronic alcohol use develops, and could be used to develop more effective treatments for alcohol addiction.