Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): role of GABA(A) receptor subtypes.
Previous reports suggest that gamma-aminobutyric acid type A (GABA(A)) receptors containing alpha1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine) is a GABA(A) receptor modulator with intrinsic efficacy in vitro at alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors, and little demonstrable intrinsic efficacy in vitro at alpha1 subunit-containing GABA(A) receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors contribute to the interoceptive effects of BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained to discriminate L-838,417 (0.3 mg/kg, i.v.) from vehicle under a 5-response fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 administration resulted in dose-dependent increases in drug-lever responding that were antagonized by the BZ-site antagonist, flumazenil. Administration of non-selective BZs, compounds with 10-fold greater affinity for alpha1 subunit-containing GABA(A) receptors compared to alpha2, alpha3, and alpha5 subunit-containing GABA(A) receptors, barbiturates and ethanol (which modulate the GABA(A) receptor via a non-BZ site), all resulted in a majority of responses on the L-838,417-paired lever (65-100% drug-lever responding). betaCCT, an antagonist that binds with 20-fold greater affinity for alpha1 subunit-containing GABA(A) receptors relative to alpha2, alpha3, and alpha5-containing GABA(A) receptors, had no significant effect on the discriminative stimulus effects of L-838,417 or the L-838,417-like effects of diazepam or zolpidem. These data suggest that efficacy at alpha2, alpha3, and/or alpha5 subunit-containing GABA(A) receptors likely are sufficient for engendering BZ-like discriminative stimulus effects.
Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA 01772-9102, USA.
Stephanie C
SC
Licata
Donna M
DM
Platt
Daniela
D
Rüedi-Bettschen
John R
JR
Atack
Gerard R
GR
Dawson
Michael L
ML
Van Linn
James M
JM
Cook
James K
JK
Rowlett
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002404:Catheterization; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D009483:Neuropsychological Tests; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012453:Saimiri; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000077334:Zolpidem
D001463:Barbiturates; D002243:Carbolines; D002492:Central Nervous System Depressants; D005464:Fluorobenzenes; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D011725:Pyridines; D011963:Receptors, GABA-A; D014230:Triazoles; D000431:Ethanol; D005442:Flumazenil; D000077334:Zolpidem; C409903:L 838,417; C043232:tert-butyl beta-carboline-3-carboxylate; D003975:Diazepam