QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.094003v1 316/3/1291    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mirza, N. R. Articles by Mathiasen, L. S. Search for Related Content PubMed PubMed Citation Articles by Mirza, N. R. Articles by Mathiasen, L. S.

BEHAVIORAL PHARMACOLOGY

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

NeuroSearch A/S, Ballerup, Denmark (N.R.M., L.S.M.); and Behavioural Neuroscience Laboratory, Institute of Psychological Sciences, University of Leeds, Leeds, England (R.J.R., L.S.M.)

The zolpidem discriminative cue is mediated by GABA_A-₁ receptors, whereas the chlordiazepoxide cue may be mediated via non-₁ GABA_A receptors because compounds with selective affinity for GABA_A-₁ receptors fully generalize to the former cue. We predicted that L-838,417 [7-tert-butyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine], a partial agonist at non-₁ GABA_A receptors and an antagonist at GABA_A-₁ receptors, would generalize to the chlordiazepoxide but not the zolpidem-discriminative cue. SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one] 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. Because SL651498 has efficacy at GABA_A-₁ receptors, we anticipated that it would generalize 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 generalization profiles of L-838,417 and SL651498 were compared with nonselective full agonists, GABA_A-₁-selective ligands zolpidem and CL218,872 [3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine], the nonselective partial agonist bretazenil, and the novel anxioselective drug ocinaplon. A nonselective partial agonist was included because L-838,417 and SL651498 are partial agonists at some GABA_A receptors, and this property may influence their generalization profiles. All nonselective full agonists and ocinaplon fully generalized to both cues. CL218,872 and zolpidem generalized to zolpidem only, whereas L-838,417 fully generalized to chlordiazepoxide only. SL651498 fully generalized 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 generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABA_A receptor subtypes.

Address correspondence to: Dr. Naheed R. Mirza, Department of In vivo Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. E-mail: max{at}neurosearch.dk