Behavioral Pharmacology and GHB Physical Dependence

描述（由申请人提供）：γ-羟基丁酸酯（GHB）是一种滥用药物，具有强效CMS抑制作用。长期服用伽马--羟丁酸可产生身体依赖性，据报告，戒断综合征类似于戒断典型的镇静催眠药（苯二氮卓类和酒精）。GHB的药理作用机制似乎涉及多个系统，包括GHB、γ-氨基丁酸（GABA）和阿片样物质。提出了三个具体目标，以进一步表征伽马-羟丁酸的行为药理学和身体依赖潜力。目的1将评估GHB给药剂量和持续时间对身体依赖性发展的影响。将在相同的持续时间内给予一定范围的GHB剂量，然后给予GABA-B拮抗剂。将描述戒断症状和对食物维持行为的影响。第二，伽马-羟丁酸剂量将保持不变，暴露时间将有所不同。将确定拮抗剂诱发的戒断行为的严重程度作为GHB给药时间的函数。目的2将检查GHB、苯二氮卓类GABA-A和GABA-B受体激动剂和拮抗剂在非依赖性、GHB依赖性和GHB戒断受试者中的行为效应。将确定每种药物增强GHB作用、促使GHB戒断和/或减轻GHB戒断的能力。这些研究将确定长期服用GHB是否会引起GHB、GABA-A和/或GABA-B受体的功能变化，如药物剂量效应函数的变化所证明的。目的3将使用24小时自我注射程序表征GHB以及前药γ-丁内酯（GBL）和1，4-丁二醇（1，4-BD）的自我给药的增强作用和模式。将比较每种药物的相对强化功效，如通过在渐进比率程序下每次注射完成的最大功输出或“断裂点”所测量的。还将评价自行注射伽马--羟丁酸、伽马-丁酸和1，4-丁二醇对身体的依赖性。这些研究将提供关于伽马--羟丁酸的行为药理学和致瘾作用的重要信息。

DESCRIPTION (provided by applicant): Gamma-hydroxybutyrate (GHB) is a drug of abuse with potent CMS depressant effects. Chronic administration of GHB can produce physical dependence and the withdrawal syndrome reportedly resembles withdrawal from classic sedative-hypnotics (benzodiazepines and alcohol). The mechanisms underlying the pharmacological actions of GHB appear to involve multiple systems including GHB, Gamma-aminobutyric acid CGABA), and opioid. Three specific aims are proposed to further characterize the behavioral pharmacology and physical dependence potential of GHB. Aim 1 will evaluate the effects of dose and duration of GHB administration on development of physical dependence. A range of GHB doses will each be administered for the same duration and then a GABA-B antagonist will be administered. Signs of withdrawal and effects on food-maintained behavior will be characterized. Second, GHB dose will be held constant and the length of exposure will be varied. The severity of antagonist-precipitated withdrawal behaviors as a function of the length of GHB administration will be determined. Aim 2 will examine the behavioral effects GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects. The ability of each drug to potentiate GHB effects, precipitate withdrawal and/or alleviate GHB withdrawal will be determined. These studies will determine if chronic GHB administration produces functional changes in GHB, GABA-A and/or GABA-B receptors as evidenced by shifts in the drug dose effect functions. Aim 3 will characterize the reinforcing effects and pattern of self- administration of GHB, and pro-drugs gamma-butyrolactone (GBL) and 1,4-butendiol (1,4-BD) using a 24-hr self-injection procedure. The relative reinforcing efficacy of each drug will be compared, as measured by the maximum work output or "breaking point" completed for each injection under a progressive ratio procedure. Physical dependence in the context of self-injection of GHB, GBL and 1,4-BD will also be evaluated. These studies will provide critical information on the behavioral pharmacology and dependence-producing effects of GHB.