CELLULAR MODELS OF ALCOHOL DEPENDENCE USING IN VIVO SYSTEMS

我们提出的研究旨在验证三个主要假设：1。的 关键神经元回路使用识别的发射器， 从脑干投射部位，作为一个关键的间接功能， Nacc神经元亚组的乙醇作用成分; 2.的 神经元本身及其内在的神经化学介质是 对于乙醇强化、依赖性和/或复发至关重要;以及3.的 一个更大的三部分神经元回路，涉及复杂的局部 腹侧被盖区、杏仁核和核团分区的相互作用 乙醇是乙醇自我给药的关键底物， 依赖和复发。为了进一步验证我们的假设，我们将 生理探针，在体内，这一途径的关键组成部分。 首先，在麻醉（氟烷）啮齿动物细胞核中识别细胞 将评估骨水泥外壳和核心对急性 给予乙醇，以及乙醇与 递质受体亚型利用多巴胺（DA），γ-氨基丁酸 酸（GABA），谷氨酸和阿片类药物通过采用受体选择性 激动剂和拮抗剂。细胞外神经生理学研究将 比较急性酒精对单细胞和多突触的影响， 慢性暴露后酒精对NAcc神经元的作用， 持续禁欲第二，来自细胞核区域的单个细胞 杏仁核的中央核和腹侧区 在氟烷麻醉下，同时研究被盖区 大鼠对急性乙醇给药的不同敏感性 以及在依赖和复发发作之后。最后，我们将记录 自发的单个单位和宏观生理活动， 在未经麻醉，自由移动的动物在训练乙醇口服自我- 给药，在乙醇依赖期间和长期给药后 禁欲这样我们就可以在单个单元或宏中确定 神经元中的生理活性是预测细胞相关性 酒精寻求行为和复发。

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.