COCAINE SELF ADMINISTRATION IN DOPAMINE KNOCKOUT MICE

研究建议使用基因靶向“敲除”小鼠来分析不同多巴胺能系统在可卡因强化效应中的作用。令人信服的药理学和神经生物学证据表明，可卡因的滥用相关效应是由多巴胺能系统介导的，基于多巴胺的策略为开发治疗可卡因滥用和依赖的新药物提供了有希望的途径。对敲除小鼠体内可卡因增强作用的机制进行系统分析，可能有助于更具体地确定设计和合成多巴胺相关药物的分子靶点。虽然作用于多巴胺转运体或d1样受体或D2样受体的药物可以改变可卡因的一些滥用相关效应，但这些蛋白质在可卡因效应中的作用尚不完全清楚。基因技术在小鼠中允许通过“敲除”其功能基因来删除单个蛋白质，这提供了一种高度特异性的工具，可能有助于阐明药理学作用。例如，D2/D3混合化合物对可卡因自我给药的改变可能是由于D2或D3单独或联合作用。在缺乏D2受体的小鼠中进行的研究将允许更清晰地分析D3受体在这种效应中的作用。建议的自我给药将：(1)检查缺乏多巴胺转运体或D1或D2受体的可卡因增强作用，(2)使用这些小鼠更精确地指定非选择性多巴胺能化合物修饰可卡因自我给药所涉及的受体机制。本提案的一个重要特点是，将对亲本近交系进行自我给药研究，并对非药物强化剂维持的应答进行研究，为敲除小鼠自我给药研究的结果提供全面的解释依据。此外，对雄性和雌性小鼠的研究将能够评估基因和药理学对可卡因自我给药影响的性别差异。总的来说，这项研究将增加我们对特定多巴胺能蛋白在可卡因滥用相关效应中的作用的理解，并有助于确定药物开发的最合适靶点。此外，将基因靶向策略与药理学和药物自我给药技术结合起来，将为今后使用更先进的遗传技术确定可卡因滥用相关影响的分子机制的研究提供一个框架。

Studies are proposed to use gene-targeted "knockout" mice to analyze the roles of different dopaminergic systems in the reinforcing effects of cocaine. Compelling pharmacological and neurobiologic evidence suggests that the abuse-related effects of cocaine are mediated by dopaminergic systems, and dopamine-based strategies provide promising avenues for development of new medications to treat cocaine abuse and dependence. The more specific identification of molecular targets for design and synthesis of dopamine-related medications may be greatly assisted by systematic analyses of mechanisms mediating cocaine's reinforcing effects in knockout mice. Although drugs acting at the dopamine transporter or at D1-like or D2- like receptors can modify some abuse-related effects of cocaine, the roles of these proteins in cocaine's effects are not fully understood. Genetic technology in mice that permits the deletion of a single protein by "knockout" of its functional gene provides a highly specific tool that may help to elucidate the roles pharmacologically. For example, the modification of cocaine self-administration by mixed D2/D3 compounds may be due to D2 or D3 actions alone or in combination. Studies in mice that lack the D2 receptor will permit a clearer analysis of the role of the D3 receptor in such effects. The proposed self-administration will: (1) examine the reinforcing effects of cocaine in mice lacking the dopamine transporter or to the D1 or D2 receptor, and (2) use these mice to specify more precisely the receptor mechanisms involved in the modification of cocaine self-administration by non-selective dopaminergic compounds. An important feature of this proposal is that self-administration studies in parental inbred strains and studies of responding maintained by a non-drug reinforcer will be conducted to provide a comprehensive basis for interpreting results of self-administration studies in knockout mice. In addition, studies in male and female mice will allow assessment of gender differences in genetic and pharmacological influences on cocaine self-administration. Overall, this research will increase our understanding of the roles of specific dopaminergic proteins in cocaine's abuse-related effects and help to identify the most appropriate targets for medications development. Moreover, integrating gene-targeting strategies with pharmacological and drug self-administration techniques will provide a framework for future studies using yet more advanced genetic technology to identify molecular mechanisms of cocaine's abuse-related effects.