Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination.
The zolpidem discriminative cue is mediated by GABA(A)-alpha1 receptors, whereas the chlordiazepoxide cue may be mediated via non-alpha1 GABA(A) receptors because compounds with selective affinity for GABA(A)-alpha1 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-alpha1 GABA(A) receptors and an antagonist at GABA(A)-alpha1 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)-alpha2 receptors, with lower efficacy at GABA(A)-alpha3 receptors and least efficacy at GABA(A)-alpha1 and GABA(A)-alpha5 receptors. Because SL651498 has efficacy at GABA(A)-alpha1 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)-alpha1-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-alpha1 GABA(A) receptors and the generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABA(A) receptor subtypes.
Mirza
N R
NR
Department of In vivo Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. max@neurosearch.dk
Rodgers
R J
RJ
Mathiasen
L S
LS
D000818:Animals; D053961:Azabicyclo Compounds; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D005793:Generalization, Psychological / Q000187:drug effects*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D021122:Protein Subunits; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D001570:Benzodiazepinones; D005464:Fluorobenzenes; D018757:GABA Modulators; D010879:Piperazines; D021122:Protein Subunits; D011724:Pyridazines; D011725:Pyridines; D011963:Receptors, GABA-A; D014230:Triazoles; C515050:zopiclone; D001569:Benzodiazepines; C021604:CL 218872; D002707:Chlordiazepoxide; D000077334:Zolpidem; C409903:L 838,417; C054626:bretazenil