ABSTRACT
We have previously demonstrated that cyclothiazide (CTZ) is a potent convulsant drug inducing robust epileptiform activity in hippocampal neurons both in vitro and in vivo. Here we further establish an animal model for CTZ-induced behavioral seizures in freely moving rats. Microinjection of CTZ into the left ventricle dose-dependently induced robust seizure behaviors within 3h after administration. At a dose of 0.75 µmol, CTZ induced Racine score IV-V seizure behaviors in 71% (n=14) of the rats were tested. In addition, CTZ also induced epileptiform EEG activity accompanying behavioral seizures. The convulsant action of CTZ on both behavior and EEG was blocked by pretreatment with clinical anticonvulsant drug diazepam (n=5). In conclusion, our results demonstrate that CTZ is capable of inducing behavioral seizures in intact animals. Since CTZ acts on both GABAergic and glutamatergic systems, this new animal epilepsy model will be useful for anticonvulsant drug testing and general epilepsy research.
Subject(s)
Behavior, Animal/drug effects , Benzothiadiazines/toxicity , Brain/drug effects , Convulsants/toxicity , Epilepsy/chemically induced , Epilepsy/physiopathology , Animals , Antihypertensive Agents/antagonists & inhibitors , Antihypertensive Agents/toxicity , Behavior, Animal/physiology , Benzothiadiazines/antagonists & inhibitors , Brain/physiopathology , Convulsants/antagonists & inhibitors , Disease Models, Animal , Evoked Potentials/drug effects , Evoked Potentials/physiology , Male , Random Allocation , Rats , Rats, Sprague-DawleyABSTRACT
The effect of alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) on Ca(2+)-sensitive, tetrodotoxin (TTX)-insensitive K(+)-stimulated [3H]-L-glutamate release from rat hippocampal synaptosomes was determined. AMPA in the presence, but not in the absence of cyclothiazide, a drug which blocks AMPA receptor desensitization, elicited a dose-dependent increase in K(+)-stimulated [3H]-L-glutamate release but had no effect on basal release. The AMPA/cyclothiazide stimulation was blocked by CNQX and by GYKI 52466, an antagonist at the cyclothiazide site. These results indicate that AMPA receptors are present on presynaptic terminals and suggest that they may play a role in the regulation of neurotransmitter release.
