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: 6805984
• 负责人: John F Neumaier
• 金额: $ 32.67万
• 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/6805984
• 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5-羟色胺系统在调节滥用药物的影响方面起着几个重要作用。 在这个建议中，我们将研究5-HT 1B和5-HT 6受体的可卡因和安非他明在大鼠中的奖励和运动刺激作用的作用，并将这些与药物成瘾的进展相关的生化适应。我们将专注于一个关键的神经元奖励电路使用尖端技术与分子和解剖精度，使我们可以辨别这些受体在这个特定的背景下的作用。这是我们的假设，在延髓投射神经元，5-HT 1B受体增加和5-HT 6受体减少精神兴奋剂的行为效应。这项建议是创新的，因为它侧重于血清素受体，以前没有得到太多的关注与药物成瘾。我们将使用的主要策略是病毒介导的基因转移，以改变5-HT 1B和5-HT 6受体的表达选择性地在中刺神经元的核壳，项目腹侧被盖区。对于5-HT 1B受体，我们将研究这些神经元传出神经中5-HT 1B受体表达改变对可卡因和苯丙胺行为的影响。由于可卡因对5-羟色胺的积累有很大的直接影响，而低剂量的安非他明主要影响多巴胺，因此我们将能够评估5-HT 1B受体在药物奖赏中的作用，而不是可卡因。我们还将使用原位杂交组织化学来研究慢性可卡因给药和停药对这两种受体在中型棘神经元中表达的影响。对于5-HT 6受体，我们将联合收割机将高选择性5-HT 6激动剂和拮抗剂局部注射到延髓核壳中与全身可卡因治疗相结合，以评估这些神经元中5-HT 6受体对药物奖赏机制的作用。我们还开发了一种5-HT 6病毒载体，使我们能够非常精确地探测这些受体在神经元中的作用。该提案的总体目标是扩展我们对5-羟色胺受体如何介导可卡因和苯丙胺成瘾特性的分子和行为理解，并确定这些受体是否可以作为治疗成瘾性的新靶点。