A novel tool for studying D3 receptors and cocaine reward

描述(申请人提供)：对毒品经历的记忆和与毒品相关的环境线索可以诱发寻求毒品和吸毒行为。目前还没有有效的药物来治疗可卡因成瘾者的复发。多巴胺(DA)介导与奖赏相关的学习，滥用药物可以改变大脑中脑边缘DA系统的奖赏回路。DA D3受体主要在边缘区域表达。我们和其他人使用了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媒介。尽管它在调节可卡因的神经生物学效应方面发挥了关键作用，但直接针对D3受体的药物仍然 仅限于临床前研究。靶向D3受体需要关于D3受体如何在药物诱导行为的各个方面起作用的精确知识，以及具有改进的D3受体特异性的药理配体。到目前为止，绝大多数研究都试图从药理上减弱对寻求药物的恢复。我们已经获得了新的初步结果，表明线索-可卡因记忆的重新巩固和消亡可能为基于D3受体的治疗提供了替代的作用窗口。这一发展建议的目的是启动研究，通过更好地了解和靶向D3受体介导的机制，扩大我们对潜在新方法的知识，以减少渴求和复发。我们建议设计并描述一种新的小鼠模型，在该模型中，D3受体的水平可以在大脑中上调或下调。然后，我们将使用这个小鼠模型，结合药理学方法和静脉注射可卡因自我给药范式，研究操纵D3受体水平或活动通过中断再巩固和加速药物诱导的奖赏记忆的消亡来减少可卡因寻求的假说。这项拟议的工作将产生重大影响，因为这些结果将为开发基于D3受体的人类新疗法，验证和改进新的D3受体激动剂和拮抗剂在减少复发方面的效用，以及研究D3受体如何促进未来发展的可卡因寻求和其他可卡因诱导行为的易感性奠定重要基础。

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.