The Role of 5-HT1B Receptors in Brain Reward Circuits

5-羟色胺是大脑中的一种神经递质，在包括成瘾在内的复杂行为中发挥着重要作用。我们之前已经证明，5-HT1B受体改变了在成瘾中发挥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。由于压力可以促进戒毒后的药物渴求和复发，我们将使用药物成瘾的啮齿动物模型来研究这种受体的作用。在这笔赠款的最初五年里，我们确定5-HT1B受体的区域表达是它们对与成瘾相关的行为的影响的关键决定因素。未来几年的一个压倒一切的主题是确定这些受体在成瘾中扮演关键角色的阶段。我们将使用结合分子和行为方法的策略来研究伏隔核投射神经元中5-HT1B受体的功能，伏核投射神经元是大脑奖励和习惯形成系统的关键组成部分。我们假设，增加5-HT1B的表达是对慢性应激的一种平衡适应，可以改善情绪障碍，但会促进药物成瘾。目的1研究社会失败应激与背侧和腹侧纹状体5-HT1B基因表达的时间相关性。因此，我们将研究使用病毒介导的基因转移通过实验增加5-HT1B受体的表达是否减少了社会失败应激对享乐状态的影响，以及表达下调是否加剧了应激诱导的相同行为的变化。在目标2中，我们将使用捕捉成瘾固有发育过程的动物模型，确定5-HT1B表达增加是否在几个关键阶段调节自我给药的动机。这两个目标构成了一个双管齐下的策略，调查行为应激体验和影响享乐状态和自我服用可卡因倾向的基因表达之间的双向关系。

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.