Received for publication August 12, 2005.
Revised December 2, 2005.
Accepted for publication December 5, 2005.

Comparative cue generalisation profiles of L-838,417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination

Abstract

The zolpidem discriminative cue is mediated by GABA_A-₁ receptors, whereas the chlordiazepoxide cue may be mediated via non-₁ GABA_A receptors, since compounds with selective affinity for GABA_A-₁ receptors only fully generalise to the former cue. We predicted that L838,417, a partial agonist at non-₁ GABA_A receptors and an antagonist at GABA_A-₁ receptors, would generalise to the chlordiazepoxide but not the zolpidem discriminative cue. SL651498 is a full agonist at GABA_A-₂ receptors, with lower efficacy at GABA_A-₃ receptors, and least efficacy at GABA_A-₁ and GABA_A-₅ receptors. Since SL651498 has efficacy at GABA_A-₁ receptors, we anticipated it would generalise to both discriminative cues. Rats were trained to discriminate either zolpidem (3 mg/kg) or chlordiazepoxide (5 mg/kg) from vehicle using a two lever operant procedure. The generalisation profiles of L838,417 and SL651498 were compared with non-selective full agonists, GABA_A-₁-selective ligands zolpidem and CL218,872, the non- selective partial agonist bretazenil, and the novel anxioselective drug ocinaplon. A non-selective partial agonist was included since L838,417 and SL651498 are partial agonists at some GABA_A receptors, and this property may influence their generalisation profiles. All non-selective full agonists and ocinaplon fully generalised to both cues. CL218,872 and zolpidem generalised to zolpidem only, whereas L-838,417 fully generalised to chlordiazepoxide only. SL651498 fully generalised to chlordiazepoxide and occasioned significant zolpidem-appropriate responding. Bretazenil was similar to SL651498. In conclusion, at this training dose, the chlordiazepoxide discriminative stimulus is mediated primarily via non-₁ GABA_A receptors, and the generalisation profiles of the ligands tested appears to correspond with their in vitro profiles at GABA_A receptor subtypes.

Key words: GABAA receptor, L-838,417, SL651498, chlordiazepoxide, drug discrimination, zolpidem