Role of sigma receptors in ethanol reinforcement

该项目将在波士顿大学丰富的神经科学社区进行，涉及Sigma受体，这是一种独特的哺乳动物结合位点，可以调节其他神经递质系统，并在大脑边缘结构中丰富表达。药理学研究表明sigma受体可调节可卡因和甲基苯丙胺的作用。最近，sigma受体也被提出调节乙醇的激励特性，这与人类酒精中毒中sigma受体多态性的发现一致。然而，直到最近，对西格玛受体系统的理解一直受到缺乏特异性的、subtj^j选择性配体或缺乏西格玛受体subt5T)es的突变小鼠模型的阻碍。此外，西格玛受体在自愿摄入或自我给药乙醇中的作用尚不清楚。目前的多学科应用使用行为学、药理学和分子技术来确定在不同的过量乙醇消耗模型中sigma受体对乙醇奖励和强化的调节作用。两种过量乙醇摄入的模型将被研究，遗传选择的酒精偏好大鼠和退出的近亲繁殖大鼠在慢性，间歇性暴露于乙醇蒸气中依赖，分别强调乙醇的积极和消极强化特性。

The project, to be conducted at the Boston University in the rich neuroscience community of Boston, concerns Sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtj^je-selective ligands or of mutant mouse models that lack sigma receptor subt5T)es. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacological, and molecular techniques to determine the modulatory role of sigma receptors on ethanol reward and reinforcement in distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied, genetically selected alcohol-preferring rats and withdrawn outbred rats niade dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethhanol self-admlnistrartation will be pharmacologically modulated (Specific Aim 1), through the administration of novel sigma receptor ligands, and molecularly (in Specific Aim 2), Through the use of sigma-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on sigm receptor protein expression in discrete limbic brains regions wil lbe investigated in Specific Aim 3. impact of chronic exposure to ethanol and of innate preference for ethanol on a receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3.