GABA-A Receptor Mechanisms in Benzodiazepine Dependence

描述（由申请人提供）： 长期使用苯二氮卓类药物（BZ）可导致耐受性，表现为药物特征性行为效应的减少，以及身体依赖性，表现为戒断综合征的发生。拟议的研究将调查不同GABAA受体亚型在恒河猴慢性BZ治疗后耐受性发展和戒断中发挥作用的程度。具体目标1将评估特定GABAA/a受体亚型在特征性BZ诱导行为中的作用，包括共济失调、镇静、运动障碍和肌肉松弛。随后，特定目标2将评价常规BZ阿普唑仑长期给药后对这些行为中每一种的耐受性。受体亚型偏好激动剂和拮抗剂将用于研究GABAA/α 1和GABAA/α 5受体亚型与BZ耐受性和戒断密切相关的假设。了解GABAA受体亚型在慢性BZ治疗后耐受和戒断中的作用，应为开发新的BZ型药物提供所需的信息，以减少身体依赖的可能性。

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.