Changes in glutamate transmission in the transition to aversion-resistant alcohol drinking

项目摘要：在向厌恶抵抗转变过程中谷氨酸神经传递的变化 饮酒（CTG） 酒精使用障碍（AUD）是美国最普遍和最昂贵的健康问题之一， 几十年的研究提供了强有力的证据表明，遗传学，特别是家族史， 酒精中毒，在AUD的发展中起着关键作用。酒精中毒是一种慢性，复发性， 进行性障碍和转变为酒精依赖的一个关键特征是厌恶的发展 抵抗性（ARD）饮酒伴随着饮酒控制的下降。内侧前额叶皮质 (MPF)大脑皮层是一个决策中心，接受来自多个皮层和边缘脑区域的输入。两 MPF的子区域被认为在向酒精依赖的转变中发挥不同的作用， (PL)和边缘下（IL）皮质，PL回路的激活增加了药物寻求，而IL中的活性 减少灭绝后的药物寻求。目前的成瘾理论表明， 饮酒与大脑区域中高多巴胺能活动的出现有关， 来自PL皮层的神经递质输入。用于研究啮齿动物ARD的常见模型是奎宁耐药模型 饮酒，其中，在乙醇饮酒史后，啮齿动物显示愿意饮用奎宁掺假 乙醇溶液。酒精偏好（P）大鼠是一个很好的资源，以模拟酒精中毒的家族史， 然而，没有研究使用这种资源来研究奎宁耐药的潜在机制。 喝酒这代表了文献中的一个关键空白，我们将在本申请中开始解决这个问题。的 该项目的长期目标是确定与ARD过渡相关的神经生物学变化， 合适的AUD模型。本部分的目的是确定谷氨酸传输的作用 在MPF的子区域内，使用P-rat作为遗传学模型， AUD模型这项工作的基本原理是，通过了解海马各部分的神经元功能， 奖励系统，我们可以开始确定机制的基础过渡到强迫性饮酒。的 中心假设指出：过渡到抗奎宁饮酒涉及增加的活动， 谷氨酸系统内PL皮质，但不是IL皮质。AIM 1研究饮酒如何导致 P-大鼠的奎宁抗性饮酒改变了IL和PL皮质中的谷氨酸传输，如通过 定量微透析目的2研究抗奎宁饮酒的发展如何改变 在饮酒期间PL和IL皮质内谷氨酸的体内释放。AIM 3将检查 PL和IL皮质局部微量注射离子型谷氨酸受体拮抗剂对 奎宁抗性与奎宁敏感P-大鼠的乙醇饮用。总的来说，这一部分的结果将有助于 为开发治疗AUDs的药物疗法奠定基础。这些结果将是双向的 信息与其他ARC组件，并作为一个集团将联合收割机，以显着推进该领域。

Project Summary: Changes in glutamate neurotransmission in the transition to aversion-resistant alcohol drinking (CTG) Alcohol use disorders (AUDs) are among the most pervasive and costly health issues in the United States and decades of research has provided strong evidence that genetics, and in particular a family history of alcoholism, plays a pivotal role in the development of AUDs. Alcoholism is a chronic, relapsing, and progressive disorder and a key feature in the transition to alcohol dependence is the development of aversion resistant (ARD) drinking accompanied by a decrease in control of alcohol drinking. The medial prefrontal cortex (MPF) is a center for decision making and receives input from multiple cortical and limbic brain regions. Two sub-regions of the MPF thought to play different roles in the transition to alcohol dependence are the prelimbic (PL) and infralimbic (IL) cortices with activation of PL circuits increasing drug seeking whereas activity in the IL decreases drug seeking after extinction. Current theories of addiction suggest that the transition to compulsive drinking is associated with the emergence of hyper-glutamatergic activity in brain regions receiving significant glutamatergic input from the PL cortex. A common model used to study ARD in rodents is quinine-resistant drinking, where, after a history of ethanol drinking, rodents show a willingness to drink quinine-adulterated ethanol solutions. The alcohol-preferring (P) rat is an excellent resource to model family history of alcoholism in rats, however, no studies have used this resource to investigate the mechanisms underlying quinine-resistant drinking. This represents a critical gap in the literature which we will begin to address in this application. The long-term goal of this project is to identify neurobiological changes associated with the transition to ARD in a suitable model of AUDs. The objective of this component is to determine the role of glutamate transmission within sub-regions of the MPF in the transition to quinine-resistant alcohol drinking using the P-rat as a genetic model of AUDs. The rationale for this work is that by understanding glutamatergic function in all parts of the reward system we can begin to identify mechanisms that underlie the transition to compulsive drinking. The Central Hypothesis states: the transition to quinine-resistant drinking involves increases in the activity of glutamate systems within the PL cortex, but not the IL cortex. AIM 1 studies how alcohol drinking leading to quinine-resistance drinking by P-rats alters glutamate transmission in the IL and PL cortices, as measured by quantitative microdialysis. AIM 2 examines how the development of quinine-resistance drinking changes the in vivo release of glutamate within the PL and IL cortices during alcohol drinking episodes. AIM 3 will examine the effects of local microinjection of ionotropic glutamate receptor antagonists into the PL and IL cortices on ethanol drinking in quinine-resistant vs. quinine-sensitive P-rats. Overall, the results of this component will help lay the foundation for developing pharmacotherapies for treating AUDs. These results will be bi-directionally informative with the other ARC components and as a group will combine to significantly advance the field.