Neural Basis of Dynorphin A and Cocaine Interaction

强啡肽 A 和可卡因相互作用的神经基础

• 批准号: 6226160
• 负责人: SAMUEL F DWORKIN
• 金额: $ 12.41万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6226160
• 关键词: Mammalia; NMDA receptors; behavior test; cocaine; conditioning; drug interactions; drug tolerance; dynorphins; microdialysis; neuropharmacology; nucleus accumbens; opioid receptor; pharmacokinetics; protein structure function; psychopharmacology; reinforcer; self medication

DESCRIPTION: (Applicant's Abstract) The objective of this project is to elucidate the neural substrates by which dynorphin A 2-17 (DYN 2-17) prevents the enhancement of the conditioned reinforcing effects of cocaine which occurs following the repeated intermittent administration of cocaine (e.g. sensitization) and determine whether the acute administration of DYN 2-17 attenuates the positive reinforcing effects of this psychostimulant. This issue will be addressed using three established animal models of drug reinforcement together with the technique of in vivo microdialysis. The three behavioral procedures include conditioned place preference, drug discrimination and self-administration. Our goals are to determine whether: 1) DYN 2-17 prevents the development of sensitization to the conditioned reinforcing effects of cocaine via a k-opioid receptor independent mechanism and if peptides with structural similarities to DYN are also effective in preventing sensitization to cocaine; 2) determine the CNS mechanisms mediating the stimulus effects of DYN 2-17 and the attenuation of the reinforcing effects of cocaine by DYN 2-17 and related peptides; 3) DYN 2-17 modulates basal and NMDA-evoked dopamine (DA) overflow within the NAC as well as alterations in DA and glutamate (GLU) overflow which occurs following the repeated administration of cocaine and; 4) the repeated administration of cocaine increases the expression of DYN 2-17 in the nucleus accumbens and other brain regions comprising the mesocorticolimbic system. All three behavioral paradigms will be used to assess changes in the behavioral effects of cocaine which occur following the administration of DYN and related peptides. Cocaine self-administration will be used to determine whether endogenous peptide levels are increased following repeated cocaine administration. Microdialysis will be used to monitor changes in basal DA and Glu overflow within the NAC as well as NMDA-evoked DA overflow within the NAC which occur following the repeated administration of DYN 2-17 and cocaine. Our overall hypothesis is that: 1) DYN 2-17 suppresses basal and NMDA-evoked DA overflow within the NAC via an opioid receptor independent mechanism and that 2) these actions underlie the efficacy of DYN 2-17 in attenuating the positive rewarding effects of cocaine and the sensitization which develops to the conditioned reinforcing effects of cocaine following repeated cocaine administration.

产品说明：本项目的目的是阐明强啡肽A2 -17（DYN 2-17）阻止可卡因的条件强化作用增强的神经基质，所述可卡因的条件强化作用在重复间歇施用可卡因（例如致敏）之后发生，并确定DYN 2-17的急性施用是否减弱这种精神兴奋剂的正强化作用。 这个问题将使用三个已建立的药物强化动物模型与体内微透析技术一起解决。 这三个行为程序包括条件性位置偏爱、药物辨别和自我管理。我们的目标是确定：1）DYN 2-17是否通过k-阿片受体非依赖性机制阻止对可卡因的条件强化效应的致敏的发展，以及与DYN具有结构相似性的肽是否也有效地阻止对可卡因的致敏;（2）确定DYN 2- 17及其相关肽介导DYN 2 - 17的刺激效应和减弱可卡因的增强效应的中枢机制; 3）DYN 2-17调节NAC内的基础和NMDA诱发的多巴胺（DA）溢出以及在重复施用可卡因后发生的DA和谷氨酸（GLU）溢出的改变; 4）重复施用可卡因增加了在丘脑核和包括中皮质边缘系统的其他脑区域中DYN 2-17的表达。所有三种行为范例将用于评估在给予DYN和相关肽后发生的可卡因行为效应的变化。 可卡因自身给药将用于确定重复可卡因给药后内源性肽水平是否增加。微透析将用于监测在DYN 2-17和可卡因重复给药后发生的NAC内基础DA和Glu溢出以及NAC内NMDA诱发的DA溢出的变化。我们的总体假设是：1）DYN 2-17通过阿片受体非依赖性机制抑制NAC内的基础和NMDA诱发的DA溢出，并且2）这些作用是DYN 2-17在减弱可卡因的正性奖励作用和在重复可卡因施用后发展为可卡因的条件强化作用的致敏作用中的功效的基础。