TOLERANCE/DEPENDENCE IN SUBSTANTIA NIGRA: ROLE OF GABA

本研究将采用一种综合的方法来研究 中枢神经系统功能，发生与长期使用中枢神经系统抑制剂， 了解其长期使用改变CNS的机制 抑制性/兴奋性音调。 各种证据的汇合，包括最近 这个实验室的研究结果表明， 网状核（SNpr）是中枢神经系统的一个重要的皮质下调节中心 兴奋性和基底神经节运动输出，是一个理想的位置， 试图将受体功能的改变与其 行为后果 SNpr是苯二氮卓类药物的主要作用部位 慢性苯二氮卓治疗后受体下调。 此外，在SNpr中突出的抑制性GABA系统也被 慢性苯二氮卓类药物治疗。 初步研究表明， SNpr对局部应用GABA的行为敏感性的改变， 慢性苯二氮卓类药物治疗后的苯二氮卓类激动剂。 的 这项研究的第一个主要目标是使用标准和 放射自显影结合技术定量和定位的变化， 慢性苯二氮卓类药物给药后的GABA受体数量。 的时间 GABA受体系统的变化过程将与那些 已经因苯二氮卓类系统而闻名。 第二个主要目标是 以SNpr函数作为评价公差范围的基底， 苯二氮卓类药物依赖及其与GABA改变的关系， 苯二氮卓受体数量，并改变功能的 GABA-苯并二氮杂卓-氯离子载体复合物。 SNpr函数将是 通过局部显微注射后的运动反应测量 苯二氮卓受体激动剂和拮抗剂，GABA受体激动剂 以及拮抗剂和印防己毒素。 这项提议的结果可能会 与已经观察到的发生在 该系统可以提供一种行为测定， 苯二氮卓类“拮抗剂”Ro 15 -1788，通过评价 将Ro 15 -1788微量注射到SNpr中。 Ro 15 -1788可沉淀 慢性苯二氮卓类药物治疗后的戒断症状， 证明是检验依赖性的有价值的工具。 该SNPR系统将 用于探索耐受性的分子和功能相关性 以及对其他CNS抑制剂的依赖，例如，巴比妥酸盐和乙醇， 其机制与GABA的改变有很好的联系， 系统，并应有助于评估其他药物或 神经递质系统在耐受机制中的作用， 依赖

This research will use an integrated approach to examine the adaptations in CNS function which occur with the prolonged use of CNS depressants, and to understand the mechanisms by which their chronic use alters CNS inhibitory/excitatory tone. Converging lines of evidence, including recent findings from this laboratory, suggest that the substantia nigra pars reticulata (SNpr) is a major subcortical regulatory center of CNS excitability and of basal ganglia motor output and is an ideal location in which to attempt to correlate alterations in receptor function with their behavioral consequences. The SNpr is a major site of benzodiazepine receptor downregulation following chronic benzodiazepine treatment. Further, the inhibitory GABA syste, prominent in SNpr, is also altered by chronic benzodiazepine treatment. Preliminary studies indicate an alteration in behavioral sensitivity in SNpr to locally applied GABA and benzodiazepine agonists following chronic benzodiazepine treatment. The first major goal of this research is to use both standard and autoradiographic binding techniques to quantitate and localize changes in GABA receptor number after chronic benzodiazepine administration. The time course of changes in the GABA receptor system will be compared to those already known for the benzodiazepine system. The second major goal is to use SNpr function as a substrate to evaluate the extent of tolerance and dependence to the benzodiazepines and its relationship to altered GABA and benzodiazepine receptor number, and to altered function of the GABA-benzodiazepine-chloride ionophore complex. SNpr function will be measured by the motor response following local microinjection of benzodiazepine receptor agonists and antagonists, GABA receptor agonists and an antagonists and picrotoxin. The results of this proposal may have bearing on the differential tolerance which has been observed to occur to the benzodiazepines in man. This system may provide a behavioral assay for the benzodiazepine "antagonist" Ro15-1788 by evaluation of the effects of microinjection of Ro15-1788 into SNpr. Ro15-1788 can precipitate abstinence signs following chronic benzodiazepine treatment and so may prove a valuable tool for examining dependence. This SNpr system will be useful for exploring the molecular and functional correlates of tolerance and dependence to other CNS depressants e.g., barbiturates and ethanol, whose mechanisms have well established links with alterations in GABA systems and should also be useful for evaluating the role of other drug or neuro-transmitter systems in the mechanisms underlying tolerance and dependence.