Imidazenil: a low efficacy agonist at alpha1- but high efficacy at alpha5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem.
Whereas advances in the molecular biology of GABA(A) receptor complex using knock-out and knock-in mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA(A) receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA(A) receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of alpha1 and alpha5 GABA(A) receptor subunits. We investigated the role of long-term activation of these GABA(A) receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA(A) receptors expressing the alpha5 subunit (imidazenil) or alpha1 subunit (zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that long-term activation of GABA(A) receptors by zolpidem and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, diazepam or zolpidem long-term treatment decreased the expression of mRNA encoding the alpha1 GABA(A) receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the alpha5 GABA(A) receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of alpha1 or alpha5 GABA(A) receptor subunit. These findings suggest that long-term activation of GABA(A) receptors containing the alpha1 or other subunits but not the alpha5 receptor subunit is essential for the induction of anticonvulsant tolerance.
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, 1601 W. Taylor St., Chicago, IL 60612, USA. jauta@psych.uic.edu
James
J
Auta
Francesco
F
Impagnatiello
Bashkim
B
Kadriu
Alessandro
A
Guidotti
Erminio
E
Costa
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000627:therapeutic use*; D001640:Bicuculline; D003975:Diazepam / Q000627:therapeutic use*; D004056:Differential Threshold / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018757:GABA Modulators / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D000077334:Zolpidem
D000927:Anticonvulsants; D018757:GABA Modulators; D007093:Imidazoles; C105490:L 655,708; D011725:Pyridines; D001569:Benzodiazepines; D000077334:Zolpidem; C082661:imidazenil; D003975:Diazepam; D001640:Bicuculline