CELLULAR MODELS OF ALCOHOL DEPENDENCE USING IN VIVO SYSTEMS

我们提出的研究旨在检验三个主要假设：1. 使用起源于已识别的递质的关键神经元电路 从脑干投射部位，起到关键的间接作用 乙醇对NACC神经元亚群的作用成分；2. 伏隔神经元本身及其内在的神经化学介质是 对酒精强化、依赖和/或复发至关重要；以及3. 涉及复杂局部的较大三部分神经元回路 VTA、杏仁核和核亚区的相互作用 伏隔是乙醇自我给药的关键底物， 依赖和故态复萌。为了进一步检验我们的假设，我们将 生理探测，在体内，这一途径的关键组成部分。 首先，在麻醉的(氟烷)啮齿类动物的细胞核中鉴定细胞 伏隔子的壳和核将被评估为它们对急性 给予乙醇以及乙醇与乙醇的选择性相互作用 利用多巴胺(DA)、γ-氨基丁酸的递质受体亚型 GABA、谷氨酸和阿片类物质的受体选择性 激动剂和拮抗剂。细胞外神经生理学研究将 急性酒精与乙醇对单细胞和多突触影响的比较 酒精对慢性酒精暴露后NAcc神经元的作用 持续的禁欲。第二，来自细胞核区域的单个细胞 伏隔核、杏仁核中央核和腹侧区域 在氟烷麻醉下，将同时研究被盖区 大鼠对急性乙醇注射的差异敏感性 以及随之而来的依赖和复发。最后，我们将录制 伏隔核自发的单单位和宏观生理活动 在未麻醉、自由活动的动物中，在训练过程中口服乙醇自我 在酒精依赖期间和之后长时间服用 禁欲。这样，我们将以单个单位或宏来确定 伏隔核的生理活动是一种预测性的细胞关联 寻找酒精的行为和复发的可能性。

Our proposed studies are designed to test three major hypothesis: 1. That critical neuronal circuits employing identified transmitters originating from brainstem projection sites, function as a critical indirect components of ethanol's actions of sub-sets of Nacc neurons; 2. That accumbens neurons per se and their intrinsic neurochemical mediators are critical for ethanol reinforcement, dependance and/or relapse; and 3. That a larger tripartite neuronal circuit involving the complex local interactions in the VTA, the amygdala, and sub-divisions of the nucleus accumbens are the critical substrates of ethanol self-administration, dependence and relapse. To further test our hypotheses we will physiologically probe, in vivo, critical components of this pathway. First, identified cells in the anesthetized (halothane) rodent nucleus accumbens shell and core will be assessed as to their response to acutely administered ethanol, and the selective interaction of ethanol with transmitter receptor sub-types utilizing dopamine (DA), gamma-aminobutyric acid (GABA), glutamate and opioids by employing receptor selective agonists and antagonists. Extracellular neurophysiological studies will compare the single cell and multi-synaptic effects of acute alcohol with the actions of alcohol on NAcc neurons following chronic exposure and sustained abstinence. Second, individual cells from regions of the nucleus accumbens, the central nucleus of the amygdala and regions of the ventral tegmental area will be studied simultaneously, in halothane anesthetized rats, for their differential sensitivity to acute ethanol administration and following episodes of dependence and relapse. Finally, we will record spontaneous single unit and macro-physiologic activity from the accumbens in unanesthetized, freely-moving animals during trained ethanol oral self- administration, during ethanol dependence and following prolonged abstinence. In this way we will determine in single unit or macro physiological activity in the accumbens is a predictive cellular correlate of ethanol-seeking behavior and relapse.