Neuropharmacological Subsrates of Alcohol Addiction

最近，我们已经证明，一个同质群体的γ-氨基丁酸（GABA）神经元在腹侧被盖区（VTA）进行适应与酒精依赖。 这项建议的总体目标是评估的作用，无论是贡献或反射，腹侧被盖区GABA神经元介导的乙醇的增强性能，在非依赖和依赖条件下。 这一建议的核心论点是，腹侧被盖区GABA神经元兴奋性的适应性变化的结果，反复暴露于急性中毒水平的乙醇，并有助于伴随乙醇强化的中脑边缘多巴胺稳态失调。 本研究旨在验证三个主要假设：1）VTA GABA神经元兴奋性、N-甲基-D-天冬氨酸（NMDA）和/或GABA受体介导的神经传递的持续改变与乙醇依赖相关：2）VTA GABA神经元兴奋性、NMDA和/或GABA神经传递的增强预示着乙醇自我给药（SA）;（3）腹侧被盖区GABA神经元兴奋性、NMDA和/或GABA神经传递的适应与酒精中毒、厌恶、强化和依赖的连续过程相一致。 我们将采用电生理学方法来确定VTA GABA神经元放电率、轴突兴奋性和/或NMDA和GABA受体介导的突触输入是否经历对慢性乙醇的适应。我们将在乙醇自我给药和乙醇操作性跑道范例中评估腹侧被盖区GABA神经元放电率、轴突兴奋性和对传入突触输入的反应。这些研究将确定是否VTA GABA神经元或其皮质边缘输入在乙醇强化过程中经历可塑性。 腹侧被盖区GABA神经元可能作为独特的集成商的会聚信息的感觉，皮层和边缘区subserving乙醇成瘾。

Recently we have demonstrated that a homogeneous population of gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) undergo adaptation in association with ethanol dependence. The overall objective of this proposal is to evaluate the role, whether contributory or reflective, of VTA GABA neurons in mediating the reinforcing properties of ethanol, under non-dependent and dependent conditions. The core thesis underlying this proposal is that adaptive changes in VTA GABA neuron excitability result from repeated exposure to acute intoxicating levels of ethanol and contribute to the dysregulation of mesolimbic dopamine homeostasis that accompanies ethanol reinforcement. Our proposed studies are designed to test three major hypotheses: 1) That persistent alterations in VTA GABA neuron excitability, N-methyl-D-aspartate (NMDA) and/or GABA receptor-mediated neurotransmission occur in association with ethanol dependence; 2) That enhancement of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission anticipates ethanol self-administration (SA); and 3) That adaptation of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission parallels the continuum of ethanol intoxication, aversion, reinforcement and dependence. We will employ electrophysiological methods to determine if VTA GABA neuron firing rate, axonal excitability and/or NMDA and GABA receptor- mediated synaptic input undergo adaptation to chronic ethanol. We will evaluate VTA GABA neuron firing rate, axonal excitability and response to afferent synaptic input during ethanol self- administration and in the ethanol operant runway paradigms. These studies will determine if VTA GABA neurons or their corticolimbic inputs undergo plasticity during ethanol reinforcement. VTA GABA neurons may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction.