cgp-36742 and Substance-Related-Disorders

Although the presence of functional GABAB receptors in mammalian brain has been known for more than 20 years, there is still only one therapeutic agent in use, baclofen, which mediates its effects directly via this receptor. However, activation of this receptor can produce numerous effects that might be amenable to drug development. Evidence from preclinical studies also suggests that antagonism of the GABAB receptor produces beneficial clinical effects.

Topics: Animals; Baclofen; Brain; Clinical Trials as Topic; Cognition; Drug Evaluation, Preclinical; Epilepsy, Absence; GABA Agonists; GABA Antagonists; Humans; Muscle Spasticity; Organophosphorus Compounds; Pain; Receptors, GABA-B; Substance-Related Disorders

Abuse of gamma-hydroxybutyrate (GHB) and its precursors is a public health concern. Gamma-butyrolactone (GBL) is found in commercially available products and, when ingested, is metabolized to GHB.. The goal was to evaluate the physical dependence potential and behavioral effects of GBL.. Vehicle and then GBL were administered continuously (24 h per da y) in baboons (Papio anubis, n=5) via intragastric catheters. GBL dosing was initiated at 100 mg/kg/day and then progressively increased stepwise by increments of 100 mg/kg to a final dose of 600 mg/kg. The number of food pellets earned, fine-motor task performance, and observed behaviors were used as dependent measures. Precipitated withdrawal was evaluated after administration of GABA-B and benzodiazepine receptor antagonists during chronic GBL dosing (400-600 mg/kg). Spontaneous withdrawal was evaluated after discontinuation of chronic GBL 600 mg/kg. Blood GHB levels were determined during chronic dosing of each GBL dose by isotope dilution assay.. Chronic GBL dose-dependently decreased food-maintained behavior, disrupted performance on the fine-motor task, and produced signs of sedation and muscle relaxation. The GABA-B antagonist SGS742 [56 mg/kg, intramuscular (IM)] precipitated a withdrawal syndrome, whereas the benzodiazepine antagonist flumazenil (5 mg/kg, IM) produced little or no effect. Signs of physical dependence were also demonstrated when chronic GBL dosing was discontinued. Analysis of plasma indicated GBL was metabolized to GHB; levels were 825 to 1,690 micromol l(-1) GHB and 2,430 to 3,785 micromol l(-1) GHB after week 1 of 400 and 600 mg/kg/day, respectively.. These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.

Topics: 4-Butyrolactone; Animals; Behavior, Animal; Catheters, Indwelling; Conditioning, Operant; Dose-Response Relationship, Drug; Flumazenil; Food; GABA Antagonists; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; Male; Motor Skills; Muscle Relaxation; Organophosphorus Compounds; Papio anubis; Receptors, GABA-A; Receptors, GABA-B; Sleep; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors