Role of 5HT6 Receptors in Drug Reward

描述（由申请人提供）： 越来越多的证据表明，5-羟色胺（5-HT）神经传递在药物成瘾的形成中起着重要的调节作用。5 HT的作用的一个有希望的靶点是5 HT 6受体（5 HT 6 Rs），因为它们在边缘脑区域（例如丘脑核（NAc））中具有高密度。因此，拟议的实验的总体目标是使用分子方法来阐明5 HT 6 Rs在调节可卡因的奖励效应中的作用。假设NAc中5-HT-6 R的过度表达将减弱可卡因诱导的条件性位置偏爱（CPP），以及可卡因和应激诱导的CPP的恢复。相反，预测NAc中5 HT 6 Rs的下调和阻断将增强可卡因诱导的CPP。最后，假设5 HT 6 Rs可以调节可卡因的奖励作用的一种方式是通过调节磷蛋白DARRP-32的磷酸化状态。这些实验将提供额外的洞察5 HT 6 Rs在药物经验依赖性行为可塑性的作用，并将有助于进一步了解的过程，介导的行为和神经生物学的变化被认为是成瘾的基础。

DESCRIPTION (provided by applicant): There is increasing evidence that serotonin (5HT) neurotransmission plays an important modulatory role in the development of drug addiction. One promising target for the actions of 5HT are the 5HT6 receptors (5HT6Rs), given their high density in limbic brain regions, such as the nucleus accumbens (NAc). The overall aim of the proposed experiments, therefore, is to use molecular approaches to elucidate the role of 5HT6Rs in modulating the rewarding effects of cocaine. It is hypothesized that overexpression of 5HT6Rs in the NAc will attenuate cocaine-induced conditioned place preference (CPP), as well as both cocaineand stress-induced reinstatement of the CPP. In contrast, it is predicted that both downregulation and blockade of 5HT6Rs in the NAc will potentiate cocaine-induced CPP. Finally, it is hypothesized that one way in which 5HT6Rs may modulate the rewarding effects of cocaine is by regulating the phosphorylation states of the phosphoprotein DARRP-32. These experiments will provide additional insight into the role of 5HT6Rs in drug experience-dependent behavioral plasticity and will contribute to the further understanding of the processes that mediate the behavioral and neurobiological changes thought to underlie addiction.