• DOI:10.1124/jpet.105.094003
• Corpus ID: 21913400

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

@article{Mirza2006ComparativeCG,
  title={Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination},
  author={Naheed R. Mirza and Robert John Rodgers and L. S. Mathiasen},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2006},
  volume={316},
  pages={1291 - 1299}
}

• N. Mirza, R. J. Rodgers, L. Mathiasen
• Published 1 March 2006
• Biology
• Journal of Pharmacology and Experimental Therapeutics

The zolpidem discriminative cue is mediated by GABAA-α1 receptors, whereas the chlordiazepoxide cue may be mediated via non-α1 GABAA receptors because compounds with selective affinity for GABAA-α1 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-α1 GABAA receptors and an antagonist at GABAA-α1 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 GABAA-α2 receptors, with lower efficacy at GABAA-α3 receptors and least efficacy at GABAA-α1 and GABAA-α5 receptors. Because SL651498 has efficacy at GABAA-α1 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, GABAA-α1-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 GABAA 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-α1 GABAA receptors and the generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABAA receptor subtypes.