The Role of Serotonin Receptors In Brain Reward Circuits

血清素受体在大脑奖励回路中的作用

• 批准号: 6727896
• 负责人: John F Neumaier
• 金额: $ 32.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727896
• 关键词: amphetamines; behavioral habituation /sensitization; brain electrical activity; cell line; cocaine; drug addiction; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; neuropsychological tests; nucleus accumbens; protein structure function; psychomotor function; receptor expression; reinforcer; serotonin receptor; transcription factor; transfection

DESCRIPTION (provided by applicant): The serotonin system in the brain plays several important roles in modulating the effects of drugs of abuse. In this proposal we will examine the roles of 5-HT1B and 5-HT6 receptors in the rewarding and motor stimulant effects of cocaine and amphetamine in rats, and correlate these to biochemical adaptations that are associated with the progression of drug addiction. We will focus on a critical neuronal reward circuit using cutting edge techniques with molecular and anatomical precision so that we can discern the role of these receptors in this specific context. It is our hypothesis that, in nucleus accumbens projection neurons, 5-HT1B receptors increase and 5-HT6 receptors decrease the behavioral effects of psychostimulants. This proposal is innovative because it focuses on serotonin receptors that have not received much previous attention in relation to drug addiction. The primary strategy that we will use is viral mediated gene transfer to alter the expression of 5-HT1B and 5-HT6 receptors selectively in medium spiny neurons of the nucleus accumbens shell that project to ventral tegmental area. For 5-HT1B receptors, we will study the effect of altered 5-HT1B receptor expression in the efferents of these neurons on cocaine and amphetamine behaviors. Since cocaine has a large, direct effect on serotonin accumulation and low dose amphetamine affects dopamine predominantly, we will be able to assess the role of 5-HT1B receptors in drug reward in general as opposed to for cocaine in particular. We will also use in situ hybridization histochemistry to study the impact of chronic cocaine administration and drug discontinuation on the expression of these two receptors in medium spiny neurons. For the 5-HT6 receptor, we will combine local injections of highly selective 5-HT6 agonists and antagonists into nucleus accumbens shell with systemic cocaine treatment to evaluate the role of 5-HT6 receptors in these neurons on drug reward mechanisms. We have also developed a 5-HT6 viral vector that will allow us to probe the role of these receptors in accumbens neurons with great precision. The overall goal of this proposal is to extend our molecular and behavioral understandings of how serotonin receptors mediate the addictive properties of cocaine and amphetamine, and to determine if these receptors might serve as novel targets for treating addiction pharmacologically.

描述（由申请人提供）：大脑中的血清素系统在调节药物滥用的影响方面起着几个重要作用。