Drug Abuse Experiments on Primates
Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons
Goodwin AK, Froestl W, Weerts EM.
Johns Hopkins Bayview, Behavioral Biology Research Center, 5510 Nathan Shock Dr., Suite 3000, Baltimore, MD 21224, USA.
Psychopharmacology (Berl) 2005 Jul;180(2):342-51. Epub 2005 Mar 1.
RATIONALE: Gamma-hydroxybutyrate (GHB) is used for the treatment of narcolepsy, but it is also a drug of abuse. The behavioral pharmacology of GHB is not well defined.
OBJECTIVES: The current study was conducted to characterize the behavioral effects of a range of GHB doses in baboons (N=4) and to evaluate whether a GABA-B receptor antagonist and a GHB receptor antagonist would block a behaviorally active dose of GHB.
METHODS: In the first experiment, GHB (32-420 mg/kg) or vehicle was administered via an intragastric catheter. Sixty min after dosing, subjects were presented with a fine-motor task and observed. Food pellets were available under a fixed-ratio schedule of reinforcement 20-h/day. In the second experiment, the GABA-B antagonist CGP36742 (10-56 mg/kg), the putative GHB antagonist NCS-382 (0.1-10 mg/kg), or vehicle were administered alone and then in combination with GHB (320 mg/kg).
RESULTS: GHB dose-dependently decreased the number of food pellets earned. Performance in the motor task was also impaired and accompanied by signs of sedation and gastrointestinal discomfort. Pretreatment with CGP36742 antagonized GHB-induced suppression of food-maintained behavior and performance on the fine-motor task. Signs of abdominal discomfort, ataxia, and muscle relaxation produced by GHB were also reduced by pretreatment with CGP36742. In contrast, pretreatment with NCS-382 sometimes restored performance in the fine-motor task and increased food-maintained behavior, but the effect was variable across doses and baboons. Some doses of NCS-382 appeared to exacerbate ataxia and gastrointestinal discomfort produced by GHB in some subjects.
CONCLUSIONS: These data indicate that while GABA-B receptors play a significant role in mediating the behavioral effects of GHB in baboon, the role of GHB receptors is less clear.
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