DIENCEPHALIC MECHANISMS OF DRUG ABUSE

药物滥用的间脑机制

• 批准号: 6817626
• 负责人: STANLEY D GLICK
• 金额: $ 27.65万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817626
• 关键词: acetylcholine; diencephalon; drug abuse; drug abuse chemotherapy; extracellular; high performance liquid chromatography; laboratory rat; mesencephalon; microdialysis; nicotinic receptors; nucleus accumbens; self medication

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.

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 α3β4 烟碱受体的药物可以减少大鼠的吗啡、甲基苯丙胺和尼古丁的自我给药。在大脑中，α3β4 烟碱受体优先位于内侧缰核和脚间核。自 20 世纪 80 年代以来，人们已经知道缰核-脚间通路作为奖励系统发挥着独立于中脑边缘通路的作用。尽管人们早已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作如何影响另一个通路。该提案的目的是检查胆碱能机制在缰核-脚间通路中的作用，作为新治疗的潜在基础。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。研究将分为三个具体目标：（1）我们将确定缰核-脚间胆碱能传递影响药物的自我给药。我们的工作假设是，局部给予内侧缰核或脚间核的烟碱拮抗剂将减弱原型滥用药物（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会增强缰核-脚间通路中的胆碱能传递。胆碱能缰核-脚间途径的激活可能是介导或调节滥用药物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缰核和/或脚间核的细胞外乙酰胆碱水平。 (3)我们将确定胆碱能缰核-脚间通路调节多巴胺能中脑边缘通路。我们的工作假设是，局部给予内侧缰核或脚间核的烟碱拮抗剂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会产生新的药物滥用治疗方法。