Behavioral Pharmacology and GHB Physical Dependence

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GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects.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