Blockade of FG 7142 kindling by anticonvulsants acting at sites distant from the benzodiazepine receptor.
Repeated administration of the beta-carboline FG 7142 results in sensitisation to its convulsant effects (chemical kindling); acutely FG 7142 is not convulsant, but following several treatments full seizures develop. It has been suggested that the increased sensitivity results from changes in benzodiazepine (BZ)/GABA receptor function. The present experiments studied the ability of BZ receptor ligands and anticonvulsant drugs with diverse mechanisms of action to block the expression and development of kindling to once daily injection of FG 7142 (40 mg/kg, i.p.) in mice. In fully kindled mice, the BZ receptor agonists clonazepam, ZK 93,423 and CL 218,872, and the antagonists flumazenil and ZK 93,426 prevented FG 7142 convulsions, as did 2 anticonvulsants, sodium valproate, possibly acting by influencing GABAergic transmission, and ethosuximide. A further two substances, MK 801 and 2-chloradenosine which act respectively via glutamatergic and purinergic mechanisms were also effective. When administered concomitantly with repeated FG 7142, all of these substances prevented or strongly reduced the development of kindling. Phenytoin and carbamazepine were ineffective in protecting against FG 7142 convulsions in kindled mice, and in preventing the development of kindling when administered repeatedly together with FG 7142. Since MK 801 and 2-chloradenosine prevented kindling, these results suggest that an interaction of FG 7142 with BZ receptors is not sufficient to induce kindling, which may instead result from secondary changes in sites distant from BZ/GABA receptors.
Stephens
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DN
Research Laboratories of Schering AG, Berlin, F.R.G.
Weidmann
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R
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002243:Carbolines; D002998:Clonazepam / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects*; D051379:Mice; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000378:metabolism*
D000927:Anticonvulsants; D002243:Carbolines; D003986:Dibenzocycloheptenes; D011724:Pyridazines; D011963:Receptors, GABA-A; D002998:Clonazepam; C035874:FG 7142; C021604:CL 218872; D016291:Dizocilpine Maleate