Role of Glutamate in Cocaine Behavioral Pharmacology

描述(由申请人提供)：了解可卡因发挥其行为影响的药理学机制对于治疗可卡因成瘾的药物开发至关重要。这项建议将在非人类灵长类动物的可卡因行为药理学的背景下描述多巴胺(DA)和谷氨酸(Glu)之间的神经药理学相互作用。多巴胺在可卡因行为效应中的作用被广泛认识，并与其成瘾特性有关。DA和Glu之间的解剖基础和功能相互作用也已经建立。Glu越来越多地被认为与可卡因对啮齿动物模型的行为影响有关。突触外Glu来源于半胱氨酸-谷氨酸转运体，调节中脑边缘通路中的多巴胺功能。这一假设是通过代谢性谷氨酸受体2/3(mGluR2/3)来实现对DA的谷氨酸能调节。拟议的实验将描述操纵转运蛋白和mGluR2/3对可卡因的神经药理学和行为影响的后果。这些实验的结果将评估转运蛋白和mGluR2/3作为可卡因药物开发的潜在靶点的有效性。

DESCRIPTION (provided by applicant): Understanding the pharmacological mechanisms by which cocaine exerts its behavioral effects is essential for medications development for treating cocaine addiction. This proposal will characterize neuropharmacological interactions between dopamine (DA) and glutamate (Glu) in the context of cocaine behavioral pharmacology in nonhuman primates. The role of DA in the behavioral effects of cocaine is widely recognized and associated with its addictive properties. Anatomical substrates and functional interactions between DA and Glu have also been established. Glu has increasingly been implicated in the behavioral effects of cocaine in rodent models. Extrasynaptic Glu, originating from the cystine-glutamate transporter, regulates dopamine function in the mesolimbic pathway. This proposal hypothesizes that glutamatergic regulation of DA occurs via metabotropic glutamate receptors 2/3 (mGluR2/3). The proposed experiments will characterize the consequences of manipulating the transporter and mGluR2/3 on the neuropharmacological and behavioral effects of cocaine. Results from these experiments will evaluate the effectiveness of the transporter and mGluR2/3 as potential targets for cocaine medications development.