DIENCEPHALIC MECHANISMS OF DRUG ABUSE

描述（由申请人提供）：本研究的长期目标是开发新的有效的药物成瘾治疗方法。我们最近发现，几种阻断胆碱能α - 3β - 4尼古丁受体的药物可以减少大鼠对吗啡、甲基苯丙胺和尼古丁的自我给药。在大脑中，α - β - 4烟碱受体优先定位于内侧束和核间核。自20世纪80年代以来，人们已经知道habenuhi - inter作为一个奖励系统。虽然人们早就知道habenuli - interpedcular通路和mesol边缘通路相互作用并可能相互调节，但很少有研究探索这是如何发生的，以及对其中一个通路的操作如何影响另一个。本提案的目的是研究胆碱能机制在habenulo- interpedontic通路中的作用，作为新治疗的潜在底物。中心假设是阻断habenuhi - interpedoric通路中的胆碱能传递将减弱药物自我给药。研究将分为三个具体目标：(1)我们将建立habenulo- interendocholinenergy transmission影响药物自我给药。我们的工作假设是，局部给药到内侧链核或脚间核的尼古丁拮抗剂，将减弱静脉内自我给药的典型滥用药物（吗啡、甲基苯丙胺和尼古丁）。(2)我们将建立滥用药物增强胆碱能在habenulo- interpedoric通路的传递。激活胆碱能habenuor - inter通路可能是介导或调节药物滥用的奖赏效应的替代或补充机制。我们的工作假设是滥用药物会提高内侧链和/或核间的细胞外乙酰胆碱水平。(3)我们将建立胆碱能通路调节多巴胺能中脑边缘通路。我们的工作假设是，烟碱拮抗剂局部施用于内侧链核或核间核，将减弱滥用药物对伏隔核细胞外多巴胺水平的影响。这里提出的工作可能最终导致新的药物滥用治疗方法。

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop new and effective treatments for drug addiction. We recently discovered that several agents blocking cholinergic alpha3beta4 nicotinic receptors reduce morphine, methamphetamine and nicotine self-administration in rats. In the brain alpha3beta4 nicotinic receptors are preferentially localized in the medial habenula and interpeduncular nucleus. Since the 1980's it has been known that the habenulo-interpeduncular pathway functions as a reward system that is separate from the mesolimbic pathway. Although it has long been known that the habenulo-interpeduncular pathway and the mesolimbic pathway interact and probably modulate each other, few studies have explored how this occurs and how manipulations of one can affect the other. The goal of this proposal is to examine the role of cholinergic mechanisms in the habenulo-interpeduncular pathway as a potential substrate for new treatments. The central hypothesis is that blocking cholinergic transmission in the habenulo-interpeduncular pathway will attenuate drug self-administration. Research will be organized into three specific aims: (1) We will establish that habenulo-interpeduncular cholinergic transmission influences drug self-administration. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the intravenous self-administration of prototypicai drugs of abuse (morphine, methamphetamine, and nicotine). (2) We will establish that drugs of abuse enhance cholinergic transmission in the habenulo-interpeduncular pathway. Activation of the cholinergic habenulo-interpeduncular pathway may be an alternate or supplementary mechanism mediating or modulating the rewarding effects of drugs of abuse. Our working hypothesis is that drugs of abuse will raise extracellular levels of acetylcholine in the medial habenula and/or interpeduncular nucleus. (3) We will establish that the cholinergic habenulo-interpeduncular pathway modulates the dopaminergic mesolimbic pathway. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the effects of abused drugs on extracellular levels of dopamine in the nucleus accumbens. The work proposed here may ultimately result in new kinds of treatments for drug abuse.