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的调解中发挥重要作用，CRF受体参与精神兴奋剂的唤醒增强特性和行为敏化。拟议研究的目的是确定CRF神经递质系统在两个边缘区（隔膜和杏仁核）中在对照和慢性可卡因给药后的膜作用机制。本项目将测试的假设，CRF激动剂和拮抗剂在控制神经元的影响是通过不同的受体介导的隔膜和杏仁核和慢性可卡因后的CRF的影响改变是由于特定的CRF受体的调制。在这些研究中，CRF、尿皮质素（一种内源性CRF样肽）、CRF（9-33）（一种CRF结合蛋白抑制剂）以及肽类和非肽类CRF受体拮抗剂将使用全贴片和细胞内锐电极记录进行分析。将比较未处理对照、盐水对照和慢性可卡因动物的电生理数据。具体目标如下：1。明确CRF、尿皮质素、CRF结合蛋白抑制剂和CRF受体拮抗剂对隔核和杏仁核神经元突触传递和膜电导的影响。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。分析CRF、尿皮质素、CRF结合蛋白抑制剂和CRF受体拮抗剂对盐水对照和慢性可卡因处理动物中的隔和杏仁核中的突触传递和膜电导的影响，以及4.确定CRF受体介导的变化发展的时间进程以及这些变化的持续性。这些研究将有助于深入了解慢性可卡因成瘾中CRF的作用机制及其在药物依赖中可能的动机作用。这些结果也可能提供关键信息，CRF的非肽和肽拮抗剂作为潜在的有效药物治疗慢性可卡因依赖。

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.