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Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons

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Abstract

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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Acknowledgements

The authors gratefully acknowledge the National Institute on Drug Abuse Drug Supply Program for the generous supply of GHB and NCS-382. CGP36742 was a gift from Novartis Pharma AG. We would also like to thank Christine Ebaugh, Kelly Loftus, Kristine Lawless, and Isis Green for their expert technical assistance.

This work is supported by the National Institute on Drug Abuse grant R01 DA14919. Dr. Goodwin’s effort on this project was supported in part by NIMH Training Grant T32 MH15330. Preliminary data were presented at the College on Problems of Drug Dependence (2003) and Society for Neuroscience (2003) annual meetings.

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  1. Johns Hopkins Bayview, Behavioral Biology Research Center, 5510 Nathan Shock Dr., Suite 3000, Baltimore, MD, 21224, USA

    Amy K. Goodwin & Elise M. Weerts

  2. Neuroscience Research Novartis Pharma AG, Basel, Switzerland

    Wolfgang Froestl

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  1. Amy K. Goodwin
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  2. Wolfgang Froestl
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Correspondence to Elise M. Weerts.

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Goodwin, A.K., Froestl, W. & Weerts, E.M. Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacology 180, 342–351 (2005). https://doi.org/10.1007/s00213-005-2165-y

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