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效应的药理学机制对于开发治疗可卡因成瘾的药物至关重要。该提案将在非人灵长类动物可卡因行为药理学的背景下表征多巴胺（DA）和谷氨酸（Glu）之间的神经药理学相互作用。DA在可卡因行为效应中的作用被广泛认可，并与其成瘾特性相关。DA和Glu之间的解剖底物和功能相互作用也已建立。在啮齿动物模型中，谷氨酸越来越多地与可卡因的行为效应有关。突触外谷氨酸，起源于胱氨酸-谷氨酸转运体，调节中脑边缘通路中的多巴胺功能。该提议假设DA的谷氨酸能调节通过代谢型谷氨酸受体2/3（mGluR 2/3）发生。拟议的实验将表征操纵转运蛋白和mGluR 2/3对可卡因的神经药理学和行为学作用的后果。这些实验的结果将评估转运蛋白和mGluR 2/3作为可卡因药物开发潜在靶点的有效性。

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.