GABA-A Receptor Mechanisms in Benzodiazepine Dependence

慢性苯二氮卓类药物（BZ）使用可导致耐受性，明显表现为特征性 药物的行为效应以及身体依赖性，通过戒断的发生而明显 综合征拟议的研究将调查不同GABAA受体亚型在多大程度上发挥作用， 在恒河猴慢性BZ治疗后耐受性发展和戒断中的作用。具体 目的1探讨特异性GABAA/a受体亚型在苯妥英钠诱导的行为中的作用， 包括共济失调、镇静、运动损伤和肌肉松弛。具体目标2将 评价在长期给予常规BZ后对这些行为中的每一种的耐受性 阿普唑仑受体亚型偏好的激动剂和拮抗剂将被用来研究这一假设 GABAA/a1和GABAA/a5受体亚型与BZ耐受和戒断密切相关。 了解GABAA受体亚型在慢性BZ耐受和戒断中的作用 治疗应该为开发新的BZ型药物提供所需的信息， 身体依赖。

Chronic benzodiazepine (BZ) use can result in tolerance, evident as a diminution in the characteristic behavioral effects of the drug,.aswell as physical dependence, evident by the occurance of awithdrawal syndrome. The proposed studies will investigate the extent to which different GABAA receptor subtypes play a role in tolerance development and withdrawal following chronic BZ treatment in rhesus monkeys. Specific Aim 1will evaluate the roles of specific GABAA/a receptor subtypes in characteristic BZ-induced behaviors, including ataxia, sedation, motor impairment, and muscle relaxation. Subsequently, Specific Aim 2 will evaluate tolerance to each of these behaviors following chronic administration of the conventional BZ alprazolam. Receptor subtype-preferring agonists and antagonists will be used to investigate the hypothesis that GABAA/a1 and GABAA/a5 receptor subtypes are critically involved in BZ tolerance and withdrawal. Understanding the role of GABAA receptor subtypes in tolerance and withdrawal following chronic BZ treatment should provide needed information for developing new BZ-type drugs with reduced liability for physical dependence.