Neural Basis of Dynorphin A and Cocaine Interaction

（申请摘要）该项目的目的是阐明dynorphin a2 -17 （dyn2 -17）阻止可卡因在反复间歇性给药（如致敏）后发生的条件强化效应增强的神经基质，并确定急性给药dyn2 -17是否会减弱这种精神兴奋剂的积极强化效应。这一问题将通过三种已建立的药物强化动物模型以及体内微透析技术来解决。三种行为程序包括条件性地方偏好、药物歧视和自我给药。我们的目标是确定：1)dyn2 -17是否通过不依赖于k-阿片受体的机制阻止对可卡因条件强化效应的致敏发展，以及与DYN结构相似的肽是否也有效阻止对可卡因的致敏；2)确定dyn2 -17介导刺激作用的中枢神经系统机制以及dyn2 -17及其相关肽对可卡因强化作用的减弱；3) dyn2 -17调节NAC内基础和nmda诱发的多巴胺（DA）溢出以及重复给药后发生的DA和谷氨酸（GLU）溢出的改变；4)反复给药可增加dyn2 -17在伏隔核和其他大脑区域的表达，包括中皮质边缘系统。所有三种行为范式将被用来评估在服用DYN和相关肽后可卡因行为效应的变化。可卡因自我给药将用于确定重复给药后内源性肽水平是否升高。微透析将用于监测NAC内基础DA和谷氨酸溢出的变化，以及重复给药dyn2 -17和可卡因后发生的nmda诱发的NAC内DA溢出。我们的总体假设是：1)dyn2 -17通过阿片受体独立的机制抑制NAC内基础和nmda诱发的DA溢出；2)这些作用是dyn2 -17在减弱可卡因的积极奖励作用和在反复服用可卡因后对可卡因的条件强化效应产生的致敏作用的基础。

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.