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The Role of 5-HT1B Receptors in Brain Reward Circuits

5-HT1B 受体在大脑奖励回路中的作用

基本信息

批准号：
7894845
负责人：
John F Neumaier
金额：
$ 34.34万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894845
关键词：
5-HT6 receptor Abstinence Affect Alcohols Animal Model Behavior Behavioral Brain Characteristics Chronic stress Cocaine Cocaine Dependence Complex Corpus striatum structure Data Development Disinhibition Dopamine Dorsal Dose Drug Addiction Drug Sensitization Exposure to Extinction (Psychology)Gene Expression Gene Transfer Grant Habits Investigation Learning Link Literature Mediating Messenger RNA Molecular Motivation Neurons Neurotransmitters Nucleus Accumbens Pattern Pharmaceutical Preparations Play Procedures Process Property Psychological reinforcement Receptor Activation Receptor Signaling Regulation Relapse Research Response to stimulus physiology Rewards Rodent Model Role Saccharin Self Administration Self-Administered Serotonin Serotonin Receptor 5-HT1B Social Impacts Staging Stress Sucrose System Technology Testing Training Ventral Striatum Ventral Tegmental Area Viral Viral Vector Withdrawal addiction cocaine exposure cocaine use disturbance in affect dopaminergic neuron drug craving drug of abuse drug reward experience hedonic motivated behavior overexpression preference receptor receptor expression research study social

项目摘要

Serotonin is a neurotransmitter in the brain that plays an important role in complex behaviors including addiction. We have previously shown that 5-HT1B receptors alter brain reward mechanisms that play a central role in addiction; these receptors also seem to be involved in the adaptation to stress. Since stress can facilitate drug craving and relapse to drug seeking after abstinence, we will examine the role of this receptor using rodent models of drug addiction. In the initial five years of this grant, we established that the regional expression of 5-HT1B receptors is a critical determinant of their effects on behaviors associated with addiction. An overriding theme in the coming years is to identify the stages at which these receptors play key roles in addiction. We will use strategies that combine molecular and behavioral approaches to investigate the function of 5-HT1B receptors in nucleus accumbens projection neurons, a key component in the brain reward and habit formation systems. We hypothesize that increased 5-HT1B expression is an allostatic adaptation to chronic stress that ameliorates mood disturbance yet facilitates drug addiction. Aim 1 investigates the temporal association between social defeat stress and 5-HT1B gene expression in dorsal and ventral striatum. We will therefore investigate whether experimentally increased 5-HT1B receptor expression using viral mediated gene transfer reduces the impact of social defeat stress on hedonic state, and whether expression knockdown exacerbates stress-induced changes in the same behavior. In Aim 2 we will determine whether increased 5-HT1B expression modulates the motivation to self administer cocaine at several key stages, using animal models that capture the developmental progression inherent to addiction. These two Aims constitute a two-pronged strategy investigating the bidirectional relationship between behavioral stress experience and gene expression that impact hedonic state and the propensity to self-administer cocaine.

血清素是大脑中的一种神经递质，在包括成瘾在内的复杂行为中起着重要作用。我们之前已经表明，5-HT1B受体改变了在成瘾中起核心作用的大脑奖励机制；这些受体似乎也参与了对压力的适应。由于压力可以促进药物渴望和戒断后重新寻求药物，我们将使用啮齿动物药物成瘾模型来研究这种受体的作用。在这项资助的最初五年，我们确定了5-HT1B受体的区域表达是其对成瘾相关行为影响的关键决定因素。未来几年最重要的主题是确定这些受体在成瘾中起关键作用的阶段。我们将使用结合分子和行为方法的策略来研究5-HT1B受体在伏隔核投射神经元中的功能，这是大脑奖励和习惯形成系统的关键组成部分。我们假设5-HT1B表达的增加是对慢性应激的一种适应，它可以改善情绪障碍，但也会促进药物成瘾。目的1研究社会失败应激与背侧纹状体和腹侧纹状体5-HT1B基因表达的时间关系。因此，我们将研究通过病毒介导的基因转移实验增加5-HT1B受体表达是否会降低社会失败应激对享乐状态的影响，以及表达敲低是否会加剧应激引起的相同行为的变化。在Aim 2中，我们将利用捕捉成瘾固有的发育过程的动物模型，确定5-HT1B表达的增加是否会在几个关键阶段调节自我服用可卡因的动机。这两个目标构成了一个双管齐下的策略，研究影响享乐状态和自我使用可卡因倾向的行为应激体验和基因表达之间的双向关系。