BENZODIAZEPINE-INDUCED GABAA RECEPTOR PLASTICITY

GABA抑制性突触系统在中枢起主要作用。 神经系统，并与人类神经和精神疾病有关 癫痫、压力、焦虑和惊恐障碍、睡眠等障碍 精神障碍和药物依赖，特别是对苯二氮卓类和乙醇的依赖。 突触后主要GABA受体参与快速抑制 神经传递是GABA/A受体(GABA)。Gabar蛋白是 在转录、翻译、 组装、细胞靶向和功能水平。内生调节 包括磷酸化、锌离子和神经活性的调节。 类固醇。Gabar是许多临床相关的已知靶点 药物，包括抗癫痫抗焦虑药，以及 镇静剂/催眠药/美容剂。其中包括广泛使用的 苯二氮卓类，巴比妥酸盐，可能还有酒精。加巴尔被广泛使用 被公认为全麻药的主要候选分子靶点 行动。它们在大脑中的主导作用使GABA可能是 伴随着普通和不同寻常的正常塑性机制 经历。通过让老鼠，或者在某些情况下，细胞受到某种程度的 被认为涉及GABAR的非凡体验，我们将 调查GABAR是否发生可塑性变化，以及分子和 长期修饰的细胞机制。尤其是慢性 大鼠暴露于苯二氮类药物，但GABAR可能升高 功能，导致耐受性，尤其是对抗癫痫作用 这些毒品。容差伴随着一个缩减的GABAR函数，缩减 苯二氮卓类药物增强GABAR功能及解偶联GABA- 苯二氮卓类药物体外结合力测定。对苯二氮卓类药物的耐受性可能 在表达缺乏正常的重组GABAR的细胞中被模仿 转录控制，并可通过暴露在大鼠身上迅速逆转 而在细胞中，通过暴露于苯二氮类拮抗剂氟马西尼。这 强烈地表明，容忍和逆转是由一种 对GABAR蛋白本身进行物理化学修饰。这个项目 将试图揭示这种可塑性的分子机制。 最终，治疗策略可以基于我们的研究，目的是 理性地防止不必要的或病理性的改变 几种神经科和精神科的GABA/A受体特征 精神错乱。

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.