Cataleptic effects of γ-hydroxybutyrate (GHB), its precursor γ-butyrolactone (GBL), and GABAB receptor agonists in mice: Differential antagonism by the GABAB receptor antagonist CGP35348

Wouter Koek, Susan L. Mercer, Andrew Coop

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Rationale: Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABAB receptor agonist baclofen. Objective: To further study the role of GABAB receptors in the effects of GHB. Materials and methods: The experiments examined the ability of the GABAB receptor antagonist CGP35348 to attenuate GHB-induced catalepsy in comparison with its ability to attenuate the cataleptic effects of GABAB receptor agonists. Results: In C57BL/6J mice, GHB, the GHB precursor gamma-butyrolactone (GBL), and the GABAB receptor agonists baclofen and SKF97541 all produced catalepsy but differed in potency (i.e., SKF97541>baclofen>GBL>GHB) and in onset of action. The cataleptic effects of drug combinations were assessed at the time of peak effect of each compound, i.e., 60 min after CGP35348 and 60, 30, 30, and 15 min after baclofen, SKF97541, GHB, and GBL, respectively. At 100 mg/kg, CGP35348 shifted the dose-response curves of baclofen and SKF97541 to the right but not those of GHB and GBL; at 320 mg/kg, CGP35348 shifted the curves of all four compounds to the right. Conclusions: The finding that CGP35348 was about threefold less potent to antagonize GHB and GBL than baclofen and SKF97541 is further evidence that the mechanisms mediating the effects of GHB and GABAB agonists are not identical. Differential involvement of GABAB receptor subtypes, or differential interactions with GABAB receptors, may possibly explain why GHB is effective for treating narcolepsy and is abused whereas baclofen is not.

Original languageEnglish (US)
Pages (from-to)407-414
Number of pages8
JournalPsychopharmacology
Volume192
Issue number3
DOIs
StatePublished - Jun 2007

Keywords

  • Baclofen
  • CGP35348
  • Catalepsy
  • GABA
  • GABA-B
  • GBL
  • GHB
  • Mice
  • SKF97541

ASJC Scopus subject areas

  • Pharmacology

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