Characterizing the Edinger-Westphal response to alcohol

本提案的总体目标是表征Edinger-Westphal核（EW）对酒精的反应。在我们的实验室和其他实验室中已经表明，EW通过各种给药途径对酒精有强烈的反应。由于EW是酒精给药的一个突出目标，因此建议的研究旨在阐明其在酒精中毒中的机制和作用。该建议的具体目的是：1）表征EW对酒精给药的神经化学反应，2）鉴定酒精给药后介导EW细胞活化的候选神经递质受体，3）鉴定EW显微注射受体拮抗剂阻断EW活化的行为效应。将使用免疫组织化学和原位技术分析神经化学。受体的鉴定将涉及各种受体拮抗剂的全身给药和随后通过c-Fos的免疫组织化学分析来分析EW活化。将使用几种常见的行为测定（即酒精敏感性测量、自发活动和焦虑测量）来评估酒精给药后EW神经活动的作用。假设EW的激活靶向于由特定受体亚型激活的特定神经元子集。进一步假设这些神经元的激活参与酒精诱导的行为效应的产生。这一建议的结果将是重要的，在了解EW激活的机制作用，并参与与中毒相关的行为。此外，这项研究将有助于寻求酒精中毒的药物治疗。

The overall goal of this proposal is to characterize the response of the Edinger-Westphal nucleus (EW) to alcohol. It has been shown in our lab and others that EW is robustly responsive to alcohol by various routes of administration. Because EW is a prominent target for alcohol administration, the proposed studies are intended to elucidate its mechanism and role in alcohol intoxication. The specific aims of this proposal are: 1) to characterize the neurochemistry of EW response to alcohol administration, 2) to identify candidate neurotransmitter receptors mediating activation of EW cells following alcohol administration, and 3) to identify behavioral effects of EW microinjected receptor antagonists blocking activation of EW. Neurochemistry will be analyzed using immunohistochemical and in situ techniques. Identification of receptors will involve the systemic administration of various receptor antagonists and subsequent analysis of EW activation by immunohistochemical analysis of c-Fos. Several common behavioral assays (i.e. alcohol sensitivity measures, locomotor activity, and anxiety measures) will be used to assess the role of EW neural activity following alcohol administration. It is hypothesized that activation of EW is targeted to a specific subset of neurons that are activated by specific receptor subtypes. It is further hypothesized that activation of these neurons is involved in the generation of alcohol-induced behavioral effects. The findings of this proposal will be important in understanding the mechanistic role of EW activation and its involvement in behaviors associated with intoxication. Furthermore, this investigation will aid in the pursuit of pharmacological treatments for alcoholism.