The Role of Serotonin Receptors In Brain Reward Circuits

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效果方面扮演着几个重要的角色。 在这项提案中，我们将研究5-HT1B和5-HT6受体在可卡因和苯丙胺对大鼠的奖赏和运动刺激作用中的作用，并将这些作用与与药物成瘾进展相关的生化适应联系起来。我们将利用分子和解剖学上的精确尖端技术，专注于关键的神经元奖赏回路，以便我们能够辨别这些受体在这一特定背景下的作用。我们的假设是，在伏核投射神经元中，5-HT1B受体增加，5-HT6受体减弱精神刺激剂的行为效应。这一建议是创新的，因为它专注于5-羟色胺受体，这些受体以前没有得到太多关注，与药物成瘾有关。我们将使用的主要策略是病毒介导的基因转移，选择性地改变伏隔核外壳投射到腹侧被盖区的中等刺神经元中5-HT1B和5-HT6受体的表达。对于5-HT1B受体，我们将研究这些神经元传出神经元中5-HT1B受体表达的变化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，而小剂量的苯丙胺主要影响多巴胺，我们将能够评估5-HT1B受体在药物奖赏中的作用，而不是特别是可卡因。我们还将使用原位杂交组织化学方法来研究长期使用可卡因和停药对培养的棘神经元中这两种受体表达的影响。对于5-HT6受体，我们将结合伏隔核壳内高选择性5-HT6激动剂和拮抗剂的局部注射以及全身可卡因治疗来评估这些神经元中5-HT6受体在药物奖励机制中的作用。我们还开发了一种5-HT6病毒载体，使我们能够非常精确地探测这些受体在伏隔神经元中的作用。这项提议的总体目标是扩大我们对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的理解，并确定这些受体是否可以作为药物治疗成瘾的新靶点。

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.