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

描述（由申请人提供）：本项目的总体目标是探索负责乙醇自我给药的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表达习惯性行为所必需的，最近的研究表明，内源性大麻素系统与习惯形成和几种形式的纹状体可塑性有关。因此，这个建议的首要假设是，长期乙醇自我管理的维持是一种习惯性行为介导的，至少部分是由背外侧纹状体中的内源性大麻素信号传导。该假设将在本申请的两个具体目的中进行测试。第一个目的将测量操作性乙醇自我管理的影响，由长埃文斯大鼠的两个内源性大麻素anandamide和2-AG的细胞外水平，在背外侧纹状体，通过体内微透析测量。第二个目标将研究大麻素CB 1受体的参与在表达习惯性操作性乙醇自我管理在Long Evans大鼠。在建立乙醇的自我给药后，大鼠将接受CB 1受体拮抗剂利莫那班输注到背外侧纹状体中，以确定这些受体在自我给药行为中的参与。总之，这些实验的结果应该增加的内源性大麻素系统在习惯性乙醇自我管理的作用的理解，并提供新的信息，有关的机制，维持习惯性自我管理的酒精。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了解慢性酒精使用发展过程中发生的大脑变化，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.