CORTICOTROPIN RELEASING FACTOR MECHANISMS AND COCAINE

描述（申请人摘要）：越来越多的证据表明，促肾上腺皮质激素释放因子（CRF）神经递质系统可能在药物依赖的动机方面发挥重要作用，CRF受体参与精神兴奋剂的唤醒增强特性和行为致敏。本研究的目的是确定在控制和慢性可卡因给药后，CRF神经递质系统在两个边缘区域，中隔和杏仁核中的膜作用机制。该项目将验证以下假设：CRF激动剂和拮抗剂在对照神经元中的作用是通过中隔和杏仁核中的不同受体介导的，慢性可卡因后CRF的改变作用是由于特定CRF受体的调节。在这些研究中，CRF、尿皮质素（一种内源性的CRF样肽）、CRF结合蛋白抑制剂CRF（9-33）以及肽和非肽CRF受体拮抗剂将使用全贴片和细胞内尖锐电极记录进行分析。电生理数据将在初始对照组、生理盐水对照组和长期使用可卡因的动物中进行比较。将讨论以下具体目标：定义CRF、尿皮质素、CRF结合蛋白抑制剂和CRF受体拮抗剂对中隔和杏仁核神经元突触传递和膜传导的影响2。通过分析特异性CRF- r1受体和非特异性拮抗剂对激动剂反应的影响，确定介导CRF作用的受体；3 .分析CRF、尿皮质素、CRF结合蛋白抑制剂和CRF受体拮抗剂对生理盐水对照和慢性可卡因治疗动物中隔和杏仁核突触传递和膜传导的影响；确定CRF受体介导的变化发展的时间进程和这些变化的持久性。建议的研究将有助于了解慢性可卡因成瘾的CRF作用机制及其在药物依赖中的可能动机作用。这些结果也可能为CRF的非肽和肽拮抗剂作为治疗慢性可卡因依赖的潜在有效药物疗法提供重要信息。

DESCRIPTION (applicant's abstract): Accumulating evidence suggests that the corticotropin releasing factor (CRF) neurotransmitter system may play a prominent role in the mediation of motivational aspects of drug dependence and that CRF receptors participate in the arousal-enhancing properties of psychostimulants and in behavioral sensitization. The objective of the proposed research is to define the membrane mechanism of action of the CRF neuro- transmitter system in control and after chronic cocaine administration in two limbic areas, the septum and the amygdala. This project will test the hypothesis that the effects of CRF agonists and antagonists in control neurons are mediated through different receptors in the septum and amygdala and that the altered effects of CRF after chronic cocaine are due to modulation of specific CRF receptors. In these studies, CRF, urocortin - an endogenous CRF-like peptide, CRF (9-33) - a CRF binding protein inhibitor, and peptide and non-peptide CRF receptor antagonists will be analyzed using whole patch and intracellular sharp electrode recording. Electrophysiological data will be compared in naive control, saline control, and chronic cocaine animals. The following specific aims will be addressed: 1. Define the effect of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists on synaptic transmission and on membrane conductance in septal and amygdala neurons, 2. Determine receptors mediating CRF actions by analyzing the effect of the specific CRF-R1 receptor and non-specific antagonists on the agonists' responses, 3. Analyze effects of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists, on synaptic transmission and membrane conductance in the septum and amygdala in saline control and chronic cocaine treated animals, and 4. Determine the time course of the development of CRF receptor-mediated changes and the persistence of these changes. The proposed studies will contribute valuable insight into the mechanisms of CRF actions in chronic cocaine addiction and its possible motivational role in drug dependence. These results may also provide critical information regarding non-peptide and peptide antagonists of CRF as potentially effective pharmacotherapies in the treatment of chronic cocaine dependence.