DIENCEPHALIC MECHANISMS OF DRUG ABUSE

描述(申请人提供)：这项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α3β4烟碱受体的药物减少了吗啡、甲基苯丙胺和尼古丁在大鼠体内的自我给药。在脑内，烟碱受体优先定位于内侧缰核和脚间核。自20世纪80年代S以来，人们已经知道缰核-脚间通路是一个独立于中脑边缘通路的奖赏系统。虽然人们早就知道缰核-脚间通路和中脑边缘通路相互作用并可能相互调节，但很少有研究探讨这种情况是如何发生的，以及其中一个通路的操纵如何影响另一个通路。这项建议的目的是研究缰核-脚间通路中胆碱能机制作为新治疗的潜在底物的作用。中心假设是，阻断缰核-脚间通路中的胆碱能传递将减弱药物的自我给药。研究将被组织成三个具体目标：(1)我们将确定缰核-脚间胆碱能传递影响药物自我给药。我们的工作假设是，尼古丁拮抗剂局部注入内侧缰核或脚间核，将减弱典型滥用药物(吗啡、甲基苯丙胺和尼古丁)的静脉自我给药。(2)我们将确定滥用药物可增强缰核-脚间通路中的胆碱能传递。胆碱能缰核-脚间通路的激活可能是调节或调节滥用药物奖赏效应的一种替代或补充机制。我们的工作假设是，滥用药物会增加内侧缰核和/或脚间核细胞外乙酰胆碱的水平。(3)我们将证实胆碱能缰核-脚间通路调节多巴胺能中脑边缘通路。我们的工作假设是，尼古丁拮抗剂局部注射到内侧缰核或脚间核，将减弱滥用药物对伏隔核细胞外多巴胺水平的影响。这里提出的这项工作可能最终会带来治疗药物滥用的新方法。

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.