Neuropharmacological Subsrates of Alcohol Addiction

最近，我们证明了腹侧被盖区(VTA)内均匀分布的伽马氨基丁酸(GABA)神经元与酒精依赖相关。这项建议的总体目标是评估在非依赖和依赖条件下，VTA GABA神经元在调节乙醇的增强特性中的作用，无论是贡献的还是反射的。支持这一建议的核心论点是，VTA GABA神经元兴奋性的适应性变化是反复暴露于急性酒精中毒水平的结果，并有助于伴随着乙醇强化而导致的中脑边缘多巴胺稳态的失调。我们的研究旨在检验三个主要假设：1)VTA GABA神经元兴奋性、N-甲基-D-天冬氨酸(NMDA)和/或GABA受体介导的神经递质的持续变化与酒精依赖有关；2)VTA GABA神经元兴奋性、NMDA和/或GABA神经递质的增强与酒精自我给药(SA)有关；以及3)VTA GABA神经元兴奋性、NMDA和/或GABA神经递质的适应与酒精中毒、厌恶、强化和依赖的连续体平行。我们将使用电生理方法来确定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经历了对慢性乙醇的适应。我们将评估VTA GABA神经元的放电率、轴突兴奋性和在乙醇自我给药和乙醇可操作跑道范例中对传入突触输入的反应。这些研究将确定VTA GABA神经元或它们的皮质边缘输入在乙醇强化过程中是否经历可塑性。VTA GABA神经元可能是酒精成瘾的感觉、皮质和边缘区域汇聚信息的独特整合者。

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.