Neuropharmacological Subsrates of Alcohol Addiction

最近，我们已经证明了腹侧被盖区（VTA）的γ -氨基丁酸（GABA）神经元均质群体与乙醇依赖相关。本提案的总体目标是评估VTA GABA神经元在非依赖性和依赖性条件下介导乙醇增强特性的作用，无论是贡献性还是反射性。该建议的核心论点是VTA GABA神经元兴奋性的适应性变化是由于反复暴露于急性酒精中毒水平，并导致伴随乙醇强化的中边缘多巴胺稳态失调。我们提出的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有关；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) VTA GABA神经元兴奋性、NMDA和/或GABA神经传递的适应性与乙醇中毒、厌恶、强化和依赖的连续体相似。我们将采用电生理学方法来确定VTA GABA神经元的放电率、轴突兴奋性和/或NMDA和GABA受体介导的突触输入是否适应慢性乙醇。我们将评估VTA - GABA神经元的放电率，轴突兴奋性和对传入突触输入的反应在乙醇自我给药和乙醇操作跑道范式。这些研究将确定VTA GABA神经元或其皮质边缘输入是否在乙醇强化过程中发生可塑性。VTA - GABA神经元可能是乙醇成瘾的感觉、皮质和边缘区域趋同信息的独特整合者。

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.