Imidazenil: an antagonist of the sedative but not the anticonvulsant action of diazepam.
Flumazenil (FLU), a specific benzodiazepine (BZ) receptor antagonist has been used in the treatment of acute BZ intoxication or the alleviation of BZ-induced withdrawal syndrome on the basis of its weak partial agonist action at GABA(A) receptors. However, given to patients, FLU can worsen diazepam-induced withdrawal syndrome by lowering seizure threshold. We therefore investigated whether imidazenil, a selective positive allosteric modulator of GABA action at GABA(A) receptors containing alpha5 subunit, can antagonize diazepam-induced sedative action and suppression of locomotor activity without affecting diazepam anti-bicuculline action. We report here that while FLU (16.5 micromol/kg) showed no effect on locomotor activity and bicuculline-induced convulsion, it completely antagonized diazepam (10.5 micromol/kg) anti-bicuculline action and the suppression of locomotor activity. However, imidazenil (0.76 micromol/kg) elicited anti-bicuculline action and was dose-dependently antagonized by FLU (16.5 and 33 micromol/kg). Furthermore, imidazenil showed no effect on path length traveled but slightly decreased (40%) horizontal activity when compared to diazepam (85%), and maintained the anti-bicuculline action of diazepam to a threshold level similar to that observed with diazepam. Whereas cross-tolerance between BZs has been reported in animals and humans, we previously reported the absence of cross-tolerance between imidazenil and diazepam. Thus, we suggest that imidazenil might be more effective than FLU at alleviating the withdrawal syndrome associated with long-term BZ administration.
Auta
James
J
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor St, Chicago, IL 60612, USA. jauta@psych.uic.edu
Costa
Erminio
E
Davis
John M
JM
Guidotti
Alessandro
A
D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors*; D001569:Benzodiazepines / Q000494:pharmacology*; D001640:Bicuculline; D003292:Convulsants / Q000037:antagonists & inhibitors; D003975:Diazepam / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D000927:Anticonvulsants; D003292:Convulsants; D018756:GABA Antagonists; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D001569:Benzodiazepines; C082661:imidazenil; D003975:Diazepam; D001640:Bicuculline