Behavioral Pharmacology and GHB Physical Dependence

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_-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,_amma-aminobutyric acid CGABA), and opioid. Three specific aims are proposed to further characterize the behavioral pharmacology and physical dependence potential of GHB. Aim 1will 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effects GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent,GHB- dependent and GHB-withdrawn subjects.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 evalauted. These studies will provide critical information on the behavioral pharmacology and dependence-producing effects of GHB.