The Role of 5-HT1B Receptors in Brain Reward Circuits

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-HT 1B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。由于压力可以促进戒毒后的药物渴求和复发寻求药物，我们将使用啮齿动物模型的药物成瘾检查这种受体的作用。在最初的五年里，我们确定了5-HT 1B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。未来几年的一个压倒一切的主题是确定这些受体在成瘾中发挥关键作用的阶段。我们将使用联合收割机结合分子和行为方法的策略来研究5-HT 1B受体在脑桥核投射神经元中的功能，脑桥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5-HT 1B表达的增加是对慢性应激的一种适应性改变，这种适应性改变可以改善情绪障碍，但有助于药物成瘾。目的1探讨社交失败应激与背侧和腹侧纹状体5-HT 1B基因表达的时间相关性。因此，我们将研究是否实验增加5-HT 1B受体表达，使用病毒介导的基因转移减少的影响，社会失败的压力对享乐状态，以及是否表达敲低加剧压力诱导的变化，在同一行为。在目标2中，我们将确定是否增加5-HT 1B表达调节动机自我管理可卡因在几个关键阶段，使用动物模型，捕捉成瘾固有的发展进程。这两个目标构成了一个双管齐下的策略，调查行为压力体验和影响享乐状态和自我管理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.