VTA DA Neuron Electrophysiology In Selected Rat Lines

描述（由申请人提供）：这一竞争延续的长期目标是确定中边缘多巴胺（DA）系统中长期自愿饮酒可能导致有害酒精消费的神经生物学机制。我们观察到，选择性饲养的P大鼠长期饮酒增加了后腹侧被盖区（VTA）自发活跃的DA神经元数量，并增加了伏隔核基底细胞外DA浓度。此外，在乙醇剥夺期间，伏隔区DA水平的改变持续存在。我们假设观察到的电生理和神经化学变化是由于VTA - DA神经元敏感性增加引起的。提出的实验旨在证明增加的灵敏度和阐明可能的机制。细胞外记录技术和微离子电泳技术将应用于未麻醉的瘫痪大鼠，以检测VTA - DA神经元上受体敏感性的变化。无净弯曲微透析实验将用于检测自由运动P大鼠后VTA中特定神经递质的基础水平，以确定VTA DA神经元的变化是否由传入神经传递的改变引起。此外，电生理和传统的微透析方法将用于检查VTA DA神经元对随后的酒精处理的反应性升高。这些研究的结果将提供对长期饮酒和酒精剥夺所产生的神经适应性的理解，并可能有助于开发酒精中毒治疗的药物干预措施。

DESCRIPTION (provided by applicant): The long-term objective of this competing continuation is the identification of neurobiological mechanisms in the mesolimbic dopamine (DA) system underlying prolonged voluntary alcohol intake that may lead to harmful alcohol consumption. We observed that chronic alcohol consumption by selectively-bred P rats increased the number of spontaneously active DA neurons in the posterior ventral tegmental area (VTA) and increased basal extracellular DA concentrations in the nucleus accumbens. Furthermore, the alterations in accumbal DA levels persisted during ethanol deprivation. We hypothesize that the observed electrophysiological and neurochemical changes resulted from an increased sensitivity of VTA DA neurons. The proposed experiments are designed to demonstrate increased sensitivity and elucidate possible mechanisms. Extracellular recording techniques and microiontophoresis will be used in unanesthetized paralyzed P rats to examine changes in the sensitivities of receptors on VTA DA neurons. No-net-flex microdialysis experiments will be used to examine basal levels of specific neurotransmitters in the posterior VTA of freely moving P rats to determine if changes in VTA DA neurons result from alterations in afferent neurotransmission. In addition, both electrophysiological and traditional microdialysis methods will be used to examine the heightened responsiveness of VTA DA neurons to subsequent alcohol administration. The results of these studies will provide an understanding of the neuroadaptations produced by chronic alcohol drinking and deprivation and may contribute to the development of pharmacological interventions for the treatment of alcoholism.