Neural Basis of Dynorphin A and Cocaine Interaction

描述：(申请人摘要)本项目的目标是阐明强啡肽A2-17(Dyn 2-17)通过哪些神经底物阻止反复间歇注射可卡因(例如致敏)后增强可卡因的条件性强化作用，并确定急性给予Dyn 2-17是否减弱了这种精神刺激剂的积极强化作用。这一问题将使用三种已建立的药物强化动物模型和体内微透析技术来解决。这三种行为程序包括条件性位置偏好、药物歧视和自我管理。我们的目标是确定：1)Dyn 2-17是否通过k-阿片受体非依赖机制阻止对可卡因条件性增强效应的敏化发展，以及与Dyn结构相似的多肽是否也有效地防止对可卡因的敏化；2)确定介导Dyn 2-17刺激效应和Dyn 2-17及其相关多肽减弱可卡因增强效应的中枢机制；3)Dyn 2-17调节NAC内基础和NMDA诱发的多巴胺(DA)溢出，以及反复给药后DA和谷氨酸(GLU)溢出的变化；4)反复使用可卡因可增加伏核和其他构成中皮质边缘系统的脑区Dyn 2-17的表达。所有这三种行为模式都将被用来评估可卡因在服用Dyn和相关多肽后行为影响的变化。可卡因自身给药将被用来确定重复给药后内源性多肽水平是否增加。微透析将被用来监测NAC内基础DA和Glu溢出的变化，以及重复给药Dyn 2-17和可卡因后NMDA引起的NAC内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机制抑制NAC内基础和NMDA诱发的DA溢出；2)这些作用是Dyn 2-17减弱可卡因的积极奖赏效应和致敏作用的基础，后者发展为反复给药后可卡因的条件性增强效应。

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.