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节中发挥重要作用，并且CRF受体参与精神兴奋剂的唤醒增强特性和行为敏化。本研究的目的是确定 CRF 神经递质系统在控制和长期服用可卡因后在两个边缘区域（隔膜和杏仁核）的膜作用机制。该项目将测试以下假设：对照神经元中的 CRF 激动剂和拮抗剂的作用是通过隔膜和杏仁核中的不同受体介导的，并且慢性可卡因后 CRF 作用的改变是由于特定 CRF 受体的调节所致。在这些研究中，将使用整个贴片和细胞内尖锐电极记录来分析 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）以及肽和非肽 CRF 受体拮抗剂。将在初始对照、盐水对照和慢性可卡因动物中比较电生理数据。将解决以下具体目标： 1. 定义 CRF、尿皮质素、CRF 结合蛋白抑制剂和 CRF 受体拮抗剂对突触传递以及隔膜和杏仁核神经元膜电导的影响， 2. 通过分析特定 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，对盐水对照和慢性可卡因治疗动物的隔膜和杏仁核中的突触传递和膜电导的影响，以及4.确定CRF受体介导的变化的发展的时间过程以及这些变化的持续性。拟议的研究将为了解 CRF 在慢性可卡因成瘾中的作用机制及其在药物依赖中可能的动机作用提供有价值的见解。这些结果还可能提供关于 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的关键信息。

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.