GABA-A Receptor Mechanisms in Benzodiazepine Dependence

描述(由申请人提供)： 长期使用苯二氮(BZ)可导致耐受性，明显表现为药物特有的行为影响的减少，以及身体依赖，发生戒断综合征就是明显的。这项拟议的研究将调查不同的GABAA受体亚型在恒河猴慢性BZ治疗后的耐受发展和戒断中的作用程度。具体目标1将评估特定的GABAA/a受体亚型在BZ诱导的特有行为中的作用，包括共济失调、镇静、运动障碍和肌肉松弛。随后，特定目标2将评估在长期服用常规BZ阿普唑仑后对这些行为的耐受性。受体亚型偏爱激动剂和拮抗剂将被用来研究GABAA/Alpha1和GABAA/Alpha5受体亚型在BZ耐受和戒断中起关键作用的假设。了解GABAA受体亚型在慢性BZ治疗后耐受和戒断中的作用，将为开发减少身体依赖倾向的BZ类新药提供必要的信息。

DESCRIPTION (provided by applicant): Chronic benzodiazepine (BZ) use can result in tolerance, evident as a diminution in the characteristic behavioral effects of the drug, as well as physical dependence, evident by the occurrence of a withdrawal 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 1 will 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/alpha1 and GABAA/alpha5 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.