Lack of generalisation between the GABAA receptor agonist, gaboxadol, and allosteric modulators of the benzodiazepine binding site in the rat drug discrimination procedure

Abstract

Introduction: The binding sites for gamma-aminobutyric acid (GABA) and GABA(A) receptor agonists are located differently from the binding sites for benzodiazepine receptor agonists. Furthermore, the major pharmacological effects of benzodiazepine receptor agonists and the GABA(A) receptor agonist gaboxadol (4,5,6,7-tetrahydrroisoxazolo(5,4-c)pyridin-3-ol, THIP) are mediated by different GABA(A) receptor subunit compositions; that is, gaboxadol may interact primarily with extra-synaptically located alpha(4)beta(2/3)delta-containing receptors and benzodiazepines with the synaptically located alpha(1)beta(2/3)gamma(2)-containing receptors.

Objectives: The aim of the present study was to address if this different receptor subtype selectivity was reflected in vivo.

Materials and methods: A two-lever liquid reinforced operant discrimination procedure was conducted. Three groups of rats were trained to discriminate gaboxadol, diazepam and zolpidem 5.5, 1.5 and 0.7 mg/kg i.p., respectively, from vehicle.

Results: Substitution tests showed that gaboxadol-trained animals failed to recognize diazepam (0.75-1.5 mg/kg), zolpidem (0.4-0.7 mg/kg), zopiclone (2.5 mg/kg), zaleplon (1.0-1.5 mg/kg) or indiplon (0.31 mg/kg). In contrast, all benzodiazepine receptor agonists, but not gaboxadol (4.5-5.5 mg/kg), generalised to the discriminative stimulus in diazepam- and zolpidem-trained animals.

Discussion: In agreement with these data, the competitive benzodiazepine receptor antagonist flumazenil (10 mg/kg s.c.) antagonised the discriminative stimulus of zolpidem but not of gaboxadol. Interaction tests showed no synergistic interaction of concomitant administration of gaboxadol and zolpidem or diazepam.

Conclusion: Previous studies have shown that gaboxadol and benzodiazepines interact with different receptor populations, and the present study confirms that in vivo functional consequences of this receptor selectivity exist in the form of differential behavioural responses in rats.