Behavioral Pharmacology and GHB Physical Dependence

描述(由申请人提供)：伽马-羟基丁酸酯(GHB)是一种滥用药物，具有强大的CMS抑郁作用。长期服用GHB会产生身体依赖，据报道，戒断综合征类似于从经典的镇静催眠药(苯二氮卓类药物和酒精)中戒断。GHB的药理作用机制似乎涉及多种系统，包括GHB、γ-氨基丁酸(CGABA)和阿片类药物。提出了三个具体的目标，以进一步表征GHB的行为药理学和身体依赖潜力。目的1将评估服药剂量和服药时间对身体依赖形成的影响。一系列的GHB剂量将在相同的持续时间内给予，然后将给予GABA-B拮抗剂。停药的迹象和对食物维持行为的影响将被表征。第二，GHB的剂量将保持不变，暴露的时间长短将不同。拮抗剂催促戒断行为的严重程度将被确定为服药时间长短的函数。目的2研究GHB、苯二氮卓类GABA-A和GABA-B受体激动剂和拮抗剂对非依赖、GHB依赖和GHB戒断受试者的行为影响。将确定每种药物增强GHB效应、加速戒断和/或减缓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，药物剂量效应功能的变化证明了这一点。目的3将用24小时的自我注射程序来描述GHB、前药γ-丁内酯(GBL)和1，4-丁二醇(1，4-BD)的增强效果和模式。每种药物的相对增强效果将被比较，以在累进比率程序下每次注射所完成的最大功输出或“断点”来衡量。还将评估自身注射GHB、GBL和1，4-BD时的身体依赖性。这些研究将提供关于GHB的行为药理学和产生依赖的影响的关键信息。

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GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects.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.