Discriminative stimulus effects of flumazenil: Perceptual masking by baclofen, and lack of substitution with gamma-hydroxybutyrate and its precursors 1,4-butanediol and gamma-butyrolactone

Wouter Koek, Lawrence P. Carter, Huifang Wu, Andrew Coop, Charles P. France

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Pigeons trained to discriminate 0.1 mg/kg flumazenil, proposed as an in-vivo model to study interactions with diazepam-insensitive γ-aminobutyric acid (GABA)A receptors, were tested with various GABAergic and non-GABAergic compounds. As a result of its pharmacological selectivity, the model was suitable for further examining previously reported flumazenil-like effects of γ-hydroxybutyrate (GHB). Flumazenil and the GABAA negative modulator Ro 15-4513 produced 82-100% flumazenil-appropriate responding. Diazepam and the direct-acting GABAA agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) produced 38-64% flumazenil-appropriate responding. GHB, its precursors 1,4-butanediol (1,4-BD) and γ-butyrolactone (GBL), and the GABAB agonists baclofen and SKF97541 produced 0-24% flumazenil-appropriate responding. Baclofen shifted the flumazenil dose-response curve to the right and down, possibly involving perceptual masking of the discriminative stimulus effects of flumazenil by agonist activity at GABAB receptors. These masking effects of baclofen were blocked by the GABAB antagonist CGP35348. When CGP35348 was given together with GHB to block its GABAB agonist effects, GHB did not produce flumazenil-appropriate responding. Conceivably, effects of GHB at non-GABAB receptors (e.g. diazepam-sensitive GABAA receptors and GHB receptors) may interfere with the expression of its flumazenil-like discriminative stimulus effects. The asymmetric substitution between GHB and flumazenil is consistent with the hypothesis that the discriminative stimulus effects of GHB consist of several components, not all of which are mimicked by flumazenil.

Original languageEnglish (US)
Pages (from-to)239-247
Number of pages9
JournalBehavioural pharmacology
Volume17
Issue number3
DOIs
StatePublished - May 2006

Keywords

  • Drug discrimination
  • Flumazenil
  • Pigeon
  • γ-hydroxybutyrate

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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