The benzodiazepine partial inverse agonist Ro15-4513 alters anticonvulsant and lethal effects of carbamazepine in amygdala-kindled rats.
Ro15-4513 (ethyl-8-azido-5,6-dihydro-5methyl-6-oxo-4H-imidazo-[1,5-a]-1,4-benzodiazepine-3-carboxylate), a benzodiazepine partial inverse agonist of the GABA(A) receptor, is known to protect against alcohol toxicities. The present study was designed to determine the role of Ro15-4513 in preventing anticonvulsant, toxic, and lethal effects of carbamazepine (CBZ) in amygdala-kindled rats. Acute treatment with CBZ (25 mg/kg, i.p.) produced anticonvulsant effects in fully kindled rats characterized by a significant decrease in afterdischarge and seizure duration and stage. Repeated administration of this high dose of CBZ induced sedation and high (56%) lethality. The anticonvulsant and sedative effects of CBZ were strikingly suppressed by pretreatment with Ro15-4513 (2.5 and 5 mg/kg, i.p.), and there was no mortality in animals co-administrated with Ro15-4513 during the entire experimental period. These results indicate that Ro15-4513 protects against CBZ-induced sedation and lethality, while suppressing the anticonvulsant effects of CBZ, suggesting a role for the GABA(A) receptor in CBZ efficacy and side effects. The potential clinical implications for CBZ-induced toxicity and overdose remain to be explored.
Zhang
Zhang-Jin
ZJ
Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. zhangjin_zhang@hotmail.com
Postma
Terri
T
Obeng
Kris
K
Russell
Shani
S
Weiss
Susan R B
SR
Post
Robert M
RM
D000345:Affinity Labels / Q000494:pharmacology*; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002220:Carbamazepine / Q000633:toxicity*; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D058785:GABA-A Receptor Agonists; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000345:Affinity Labels; D000927:Anticonvulsants; D001386:Azides; D058785:GABA-A Receptor Agonists; D001569:Benzodiazepines; D002220:Carbamazepine; C042957:Ro 15-4513