Neuropharmacological substrates of alcohol addiction

描述(申请人提供)：我们在腹侧被盖区(VTA)发现了一个同质的γ-氨基丁酸(GABA)神经元群体，这些神经元经历了与酒精依赖相关的适应。我们最近报道，VTA GABA神经元是由连接蛋白-36缝隙连接连接的大脑腹侧GABA神经元的一个更大的电子网络的一部分，该网络的电耦合被多巴胺通过D2受体介导的腺苷环化酶激活而增强，并且对低剂量的乙醇敏感。我们推测，VTA GABA神经元及其形成的电网络可能是酒精成瘾的感觉、皮质和边缘区域汇聚信息的独特集成者。这项应用的总体目标是扩大我们对这类特定类型的皮质边缘GABA神经元在调节乙醇的醉人和奖赏特性中的作用的评估。这一观点的核心观点是，VTA GABA神经元是酒精自我给药的基础，VTA GABA神经元兴奋性和电突触传递的适应性变化是反复接触条件和/或非条件乙醇的结果，并有助于伴随酒精成瘾的中脑边缘稳态的失调。我们提出的体内和体外研究旨在检验四个主要假设：1)VTA GABA神经元的活动与酒精自我给药相关；2)VTA GABA神经元的受损破坏了乙醇的自我给药；3)VTA GABA神经元之间的缝隙连接传递，或VTA GABA神经元缝隙连接的谷氨酸(GLU)、GABA或DA突触调制对酒精敏感；以及4)NMD A、非NMDA、GABA、DA受体或连接蛋白-36缝隙连接蛋白基因表达的持续变化平行于突触适应的可塑性，这是酒精奖励和依赖的生理表现。

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.