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，具有有效的CMS抑制作用。长期服用GHB可产生身体依赖，据报道，戒断综合症类似于传统镇静催眠药（苯二氮卓类药物和酒精）戒断。GHB的药理作用机制似乎涉及多个系统，包括GHB、γ -氨基丁酸（CGABA）和阿片类药物。提出了三个具体目标，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GHB给药剂量和持续时间对身体依赖发展的影响。不同剂量的GHB将在相同的时间内使用，然后使用GABA-B拮抗剂。戒断症状和对食物维持行为的影响将被描述。第二，GHB剂量将保持不变，暴露时间将有所不同。拮抗剂沉淀戒断行为的严重程度与GHB给药时间的关系将被确定。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对非依赖性、GHB依赖性和GHB戒断性受试者的行为影响。将确定每种药物增强GHB效应、加速戒断和/或减轻GHB戒断的能力。这些研究将确定慢性GHB给药是否会产生GHB、GABA-A和/或GABA-B受体的功能变化，这可以通过药物剂量效应功能的变化来证明。目的3将通过24小时的自我注射过程，描述GHB和前药-丁内酯（GBL）和1,4-丁烯二醇（1,4- bd）的强化作用和模式。将比较每种药物的相对强化效果，通过在递进比率程序下每次注射完成的最大功输出或“断点”来衡量。在自我注射GHB、GBL和1,4- bd的情况下，身体依赖性也将被评估。这些研究将为GHB的行为药理学和依赖性效应提供重要信息。

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GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects.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