A possible role of a GABAergic mechanism in the convulsant action of RO5-4864.
The purpose of the present investigation was to determine the possible role of GABAergic mechanism in the convulsant action of RO5-4864. Benzodiazepines (BZ) and other agents which facilitate central GABAergic transmission delayed the onset of facial and forelimb clonus, whereas tonic hind limb extension was blocked in a dose-dependent manner. RO5-4864-induced convulsions were blocked by diazepam, clonazepam, pentobarbital, ethanol and amino-oxyacetic acid (AOAA). RO5-4864-induced convulsions were not blocked by the BZ antagonist RO15-1788. Specifically, RO15-1788 caused a decrease in the onset of severity component of tonic seizures, which tended to become generalized and precipitated in a tonic extension of the hindlimbs. Further, subconvulsive doses of a direct GABA receptor antagonist, bicuculline, enhanced the proconvulsant action of RO5-4864, indicating thereby a potential antagonism of the central GABAergic transmission. These observations strongly suggest that RO5-4864 probably elicits convulsions by selective impairment of the GABAergic transmission.
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D001570:Benzodiazepinones; D003292:Convulsants; D018756:GABA Antagonists; C028513:4'-chlorodiazepam; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline