Development of tolerance to clobazam in fully kindled rats: effects of intermittent flumazenil administration.
The effects of acute and chronic treatment with the 1,5-benzodiazepine, clobazam, were studied on fully kindled amygdaloid seizures in rats. After acute dosing, clobazam significantly reduced all parameters of kindled seizures (seizure severity, seizure duration, duration of amygdalar afterdischarges) at doses of 7.5 or 10 mg/kg i.p. 'Active' plasma concentrations of clobazam ranged between 300-800 ng/ml. The elimination half-life of clobazam in plasma was about 1 h. Only very low (10-75 ng/ml) levels of the major metabolite, N-desmethylclobazam, were detected in rats. Administration of N-desmethylclobazam indicated that plasma concentrations of at least 300 ng/ml were necessary for anticonvulsant effects. During chronic administration of clobazam, 10 mg/kg 3 times daily, marked tolerance developed to the anticonvulsant and adverse (ataxiogenic and sedative) effects of the benzodiazepine. The experiment was repeated using a different protocol with minimized environmental stimuli and no amygdala stimulation during chronic clobazam administration. The loss of effects on seizure severity and motor function was similar to the first chronic experiment, whereas the loss of effects on seizure and afterdischarge duration was less marked. This indicates that conditioning of 'learned tolerance' is partly involved in clobazam tolerance in kindled rats. Intermittent injection of the benzodiazepine receptor antagonist, flumazenil, 5 mg/kg i.p. every third day, did not alter the loss of pharmacodynamic effects during chronic treatment with clobazam, but seemed to prevent hyperexcitation and other abstinence symptoms in the withdrawal period. The data indicate that periodic injection of a benzodiazepine receptor antagonist does not represent a possible therapeutic approach for preventing the development of tolerance during long-term benzodiazepine exposure.
Löscher
W
W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Rundfeldt
C
C
D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000078306:Clobazam; D004361:Drug Tolerance; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D005260:Female; D005442:Flumazenil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006993:Hypnotics and Sedatives; D007274:Injections, Intraperitoneal; D007696:Kindling, Neurologic / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000523:psychology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D000078306:Clobazam; D005442:Flumazenil; C024581:N-desmethylclobazam