VTA DA Neuron Electrophysiology In Selected Rat Lines

描述(由申请人提供)：这项竞争性延续的长期目标是确定中脑边缘多巴胺(DA)系统中可能导致有害酒精消费的长期自愿酒精摄入背后的神经生物学机制。我们观察到长期饮酒使伏核腹后被盖区(VTA)自发活动的DA神经元数量增加，伏隔核胞外基础DA浓度增加。此外，伏隔区DA水平的变化在酒精剥夺期间持续存在。我们假设，所观察到的电生理和神经化学变化是由于VTA DA神经元的敏感性增加所致。拟议的实验旨在证明提高了敏感性并阐明了可能的机制。细胞外记录技术和微离子导入技术将在未麻醉的瘫痪P鼠身上使用，以检测VTA DA神经元上受体敏感性的变化。本实验将利用无网状柔性微透析实验检测自由活动P鼠后VTA内特定神经递质的基础水平，以确定VTA DA神经元的变化是否源于传入神经传递的改变。此外，电生理和传统的微透析方法都将被用来检测VTA DA神经元对随后的酒精注射的高反应性。这些研究的结果将提供对长期饮酒和剥夺酒所产生的神经适应的了解，并可能有助于开发治疗酒精中毒的药物干预措施。

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.