Neuropharmacological substrates of alcohol addiction

描述（由申请人提供）：我们已经在腹侧被盖区（VTA）发现了一个均匀的y-氨基丁酸（GABA）神经元群体，它们经历了与乙醇依赖相关的适应。我们最近报道了VTA GABA神经元是腹侧GABA神经元电网络的一部分，该电网络由连接蛋白-36间隙连接连接，多巴胺通过D2受体介导的腺苷酸环化酶激活增强其电偶联，并且对低剂量乙醇敏感。我们假设VTA GABA神经元及其形成的电网络可能是来自感觉、皮质和边缘区域的信息的独特整合者，为乙醇成瘾服务。该应用的总体目标是扩展我们对中皮质边缘GABA神经元在介导乙醇中毒和奖励特性中的作用的评估。该建议的核心论点是，VTA GABA神经元是乙醇自我给药的基础，VTA GABA神经元兴奋性和突触电传递的适应性变化是由反复暴露于偶然和/或非偶然乙醇引起的，并导致伴随酒精成瘾的中脑边缘稳态失调。我们提出的体内和体外研究旨在验证四个主要假设：1)VTA GABA神经元活动与乙醇自我给药相关；2) VTA - GABA神经元的损伤破坏了乙醇的自我给药；3) VTA GABA神经元间隙连接传递，或谷氨酸（GLU）、GABA或DA突触调节VTA GABA神经元间隙连接，对乙醇敏感；4) NMDA、非nmda、GABA、DA受体或连接蛋白36间隙连接蛋白基因表达的持续改变与突触适应的可塑性相似，而突触适应是酒精奖励和依赖的生理表现的基础。

DESCRIPTION (provided by applicant): We have identified a homogeneous population of y-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) that undergo adaptation in association with ethanol dependence. We have recently reported that VTA GABA neurons form part of a larger electrical network of ventral brain GABA neurons linked by connexin-36 gap junctions whose electrical coupling is enhanced by dopamine via D2 receptor-mediated activation of adenylate cyclase, and sensitive to low-dose ethanol. We hypothesize that VTA GABA neurons, and the electrical network they form, may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction. The overall objective of this application is to extend our evaluation of the role of this specific class of mesocorticolimbic GABA neurons in mediating the intoxicating and rewarding properties of ethanol. The core thesis underlying this proposal is that VTA GABA neurons underlie ethanol self-administration and that adaptive changes in VTA GABA neuron excitability and electrical synaptic transmission result from repeated exposure to contingent and/or non-contingent ethanol and contribute to the dysregulation of mesolimbic homeostasis that accompanies alcohol addiction. Our proposed in vivo and in vitro studies are designed to test four major hypotheses: 1) That VTA GABA neuron activity correlates with ethanol self-administration; 2) That lesioning VTA GABA neurons disrupts ethanol self-administration; 3) That gap junction transmission between VTA GABA neurons, or glutamate (GLU), GABA, or DA synaptic modulation of VTA GABA neuron gap junctions, is sensitive to ethanol; and 4) That persistent alterations in the gene expression of NMD A, non-NMDA, GABA, DA receptors, or connexin-36 gap junction proteins parallels the plasticity in synaptic adaptation that underlies the physiological manifestations of alcohol reward and dependence.