A novel tool for studying D3 receptors and cocaine reward

描述（由申请人提供）：药物经验的记忆和药物相关的环境线索可以引发药物寻求和服用行为。没有有效的药物治疗可卡因成瘾者的复发。多巴胺（DA）介导奖赏相关学习，药物滥用可改变中脑边缘DA系统的奖赏回路。DA D3受体优先在边缘区表达。我们和其他人已经使用D3受体突变小鼠和D3受体选择性拮抗剂来证明这些受体是可卡因奖赏效应的主要介体。尽管它在介导可卡因的神经生物学作用中起着关键作用，但是直接靶向D3受体的药物仍然是 仅限于临床前研究。靶向D3受体需要精确了解D3受体如何促进药物诱导行为的各个方面以及具有改善的D3受体特异性的药理学配体。到目前为止，绝大多数研究都试图减少重新吸毒。我们已经获得了新的初步结果，提示可卡因记忆的重新巩固和消退可能为基于D3受体的治疗提供替代作用窗口。这项发展提案的目的是启动研究，通过更好地理解和靶向D3受体介导的机制，扩大我们对减少渴望和复发的潜在新方法的了解。我们建议设计和表征一种新的小鼠模型，其中D3受体的水平可以在大脑中上调或下调。然后，我们将使用该小鼠模型，连同药理学方法和静脉内可卡因自我给药范例，来研究操纵D3受体水平或活性通过中断再巩固和加速药物诱导的奖赏记忆的消退来减少可卡因寻求的假设。拟议的工作将产生很大的影响，因为这些结果将为开发新的基于D3受体的人类疗法奠定重要的基础，验证和改善新的D3受体激动剂和拮抗剂在减少复发方面的效用，并调查D3受体如何有助于发展可卡因寻求和其他可卡因诱导的行为。

DESCRIPTION (provided by applicant): Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors. There are no effective medications for treating relapse in cocaine addicts. Dopamine (DA) mediates reward-related learning and drugs of abuse can change reward circuits in the brain mesolimbic DA system. DA D3 receptors are preferentially expressed in limbic regions. We and others have used D3 receptor mutant mice and D3 receptor-selective antagonists to demonstrate that these receptors are a major mediator of the rewarding effects of cocaine. Despite its key role in mediating the neurobiological effects of cocaine, medications directly targeting D3 receptors, however, are still limited to preclinical studies. Targeting D3 receptors requires precise knowledge on how D3 receptors contribute to all aspects of drug-induced behaviors and pharmacological ligands with improved D3 receptor specificity. The vast majority of studies so far have attempted to pharmacologically attenuate reinstatement to drug-seeking. We have obtained new preliminary results suggesting that reconsolidation and extinction of cue-cocaine memories may provide alternative action windows for D3 receptor-based therapies. The objective of this developmental proposal is to initiate studies to expand our knowledge on potential new ways to reduce craving and relapse by better understanding and targeting D3 receptor-mediated mechanisms. We propose to engineer and characterize a novel mouse model in which levels of D3 receptors can be up- or down-regulated in the brain. We will then use this mouse model, together with pharmacological methods and the intravenous cocaine self-administration paradigm, to investigate the hypothesis that manipulating D3 receptor levels or activity reduces cocaine- seeking by interrupting the reconsolidation and accelerating the extinction of drug-induced reward memory. The proposed work will have a high impact in that the results will lay important groundwork for developing novel D3 receptor-based therapies in humans, for validating and improving utilities of new D3 receptor agonists and antagonists in reducing relapse, and for investigating how D3 receptors contribute to vulnerability to developing cocaine-seeking and to other cocaine-induced behaviors in the future.