BENZODIAZEPINE-INDUCED GABAA RECEPTOR PLASTICITY

GABA抑制性突触系统在中枢神经系统中起着重要作用。 神经系统，并涉及人类神经和精神 癫痫、压力、焦虑和恐慌症等疾病， 疾病和药物依赖，特别是苯二氮卓类和乙醇。 参与快速抑制的主要突触后GABA受体 GABA/A受体（GABA/A receptor）GABAR蛋白是 在转录，翻译， 组装、细胞靶向和功能水平。内源性调节 包括通过磷酸化、锌离子和神经活性的调节， 类固醇. GABAR是许多临床相关疾病的已知靶点， 药物，包括抗癫痫药和抗焦虑药， 镇静/催眠/美容剂。其中包括广泛使用的 苯二氮卓类巴比妥类药物可能还有酒精GABAR广泛 被公认为全身麻醉药的主要候选分子靶点 行动上它们在大脑中的主要作用使得GABA可能在 伴随着普通和非凡的正常可塑性机制 经验通过对老鼠，或者在某些情况下，细胞， 被认为涉及GABAR的非凡经历，我们将 研究GABAR是否发生塑性变化， 长期修饰的细胞机制。特别是慢性 大鼠暴露于苯二氮卓类药物，但可能是GABAR升高 功能，导致耐受性，特别是抗癫痫作用的 这些药物。耐受性伴随GABAR功能降低， 苯二氮卓类药物增强GABAR功能，以及GABA- 体外测定的苯并二氮杂卓结合。对苯二氮卓类药物的耐受性 在表达重组GABAR的细胞中被模拟， 转录控制，并可通过暴露在大鼠中迅速逆转 以及通过暴露于苯二氮拮抗剂氟马西尼而在细胞中。这 强烈表明，耐受性和逆转是由一个 GABAR蛋白本身的物理化学修饰。这个项目 将试图发掘这种可塑性的分子机制。 最终的治疗策略可以基于我们的研究， 合理地防止不必要的或病理性的变化， 几种神经和精神疾病的GABA/A受体特征 紊乱

The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA/A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic anti-anxiety, and sedative/hypnotic/aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in the brain makes GABA likely players in the normal plasticity mechanisms that accompany ordinary and extraordinary experiences. By subjecting rats, or in some cases, cells, to somewhat extraordinary experiences that are considered to involve GABAR, we will investigate whether plastic changes in GABAR occur and the molecular and cellular mechanisms of the long-term modifications. In particular, chronic exposure of rats to benzodiazepines, but probably an elevation of GABAR function, leads to tolerance, especially to the anti-epileptic actions of these drugs. Tolerance is accompanied by a reduced GABAR function, reduced enhancement of GABAR function by benzodiazepines, and uncoupling of GABA- benzodiazepine binding measured in vitro. Tolerance to benzodiazepines can be mimicked in cells expressing recombinant GABAR that lack normal transcriptional control, and can be reversed rapidly by exposure in rats and in cells by exposure to the benzodiazepine antagonist flumazenil. This strongly suggests that the tolerance and reversal result from a physicochemical modification of the GABAR protein itself. This project will attempt to unearth this molecular mechanisms of plasticity. Ultimately therapeutic strategies could be based on our studies, aimed rationally at preventing the unwanted or pathological alterations in GABA/A receptors characteristic of several neurological and psychiatric disorders.