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DIENCEPHALIC MECHANISMS OF DRUG ABUSE

药物滥用的间脑机制

基本信息

批准号：
7433710
负责人：
STANLEY D GLICK
金额：
$ 25.69万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-15 至 2012-06-30
项目状态：
已结题

项目摘要

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，几种药物阻断胆碱能α 3 β 4烟碱受体减少吗啡，甲基苯丙胺和尼古丁自我管理的大鼠。在大脑中，α 3 β 4烟碱受体优先定位于内侧缰核和脚间核。自20世纪80年代以来，已经知道缰-脚间通路作为与中脑边缘通路分离的奖励系统起作用。虽然人们早就知道缰-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是如何发生的，以及如何操纵一个可以影响另一个。这项建议的目的是研究胆碱能机制在缰-脚间通路中的作用，作为新治疗的潜在底物。中心假设是，在缰-脚间通路中阻断胆碱能传递将减弱药物自我给药。研究将被组织成三个具体目标：（1）我们将建立缰-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，局部给药到内侧缰核或脚间核，将减弱静脉内自我管理的原型药物滥用（吗啡，甲基苯丙胺，尼古丁）。(2)我们将确定滥用药物增强了缰核-脚间通路中的胆碱能传递。胆碱能缰-脚间通路的激活可能是一种替代或补充机制，介导或调节滥用药物的奖赏效应。我们的工作假设是，滥用药物将提高细胞外水平的乙酰胆碱在内侧缰核和/或脚间核。(3)我们将建立胆碱能缰-脚间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，局部给药到内侧缰核或脚间核，将减弱滥用药物对细胞外多巴胺水平的影响，在丘脑核。这里提出的工作可能最终导致新的药物滥用治疗方法。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of 18-methoxycoronaridine on ghrelin-induced increases in sucrose intake and accumbal dopamine overflow in female rats.

DOI：
10.1007/s00213-010-2132-0
发表时间：
2011-05
期刊：
PSYCHOPHARMACOLOGY
影响因子：
3.4
作者：
McCallum, Sarah E.;Taraschenko, Olga D.;Hathaway, Ethan R.;Vincent, Melanie Y.;Glick, Stanley D.
通讯作者：
Glick, Stanley D.

18-Methoxycoronaridine, a potential anti-obesity agent, does not produce a conditioned taste aversion in rats.

18-Methoxycoronaridine 是一种潜在的抗肥胖剂，不会在大鼠中产生条件性味觉厌恶。