The benzodiazepine receptor partial agonist Ro 19-8022 suppresses generalized seizures without impairing motor functions in developing rats.
The action of a partial benzodiazepine receptor agonist Ro 19-8022 [(R)-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbo nyl] -2-pyrrolidine-methanol] in doses from 0.01 to 150 mg/kg was studied using motor seizures induced by pentylenetetrazol (PTZ) in rats 7, 12, 18, 25 and 90 days old. Generalized tonic-clonic seizures were suppressed in all age groups, the three youngest groups being more sensitive than older animals. The highest dose of Ro 19-8022 did not exhibit anticonvulsant action in the 25-day-old rats. The other types of seizures (minimal clonic) induced by PTZ were suppressed by Ro 19-8022 only in 18-day-old and older rats in which PTZ reliably elicited these types of seizures. The doses of 50, 100 and 150 mg/kg were ineffective against minimal seizures. On the contrary, incidence of minimal seizures was significantly increased by Ro 19-8022 in 7-and 12-day-old rat pups. Motor performance of rat pups was not compromised by Ro 19-8022 (0.5 and 50 mg/kg) in contrast to the full agonist midazolam (1 and/or 2 mg/kg). The duration of anticonvulsant effects studied with a dose of 0.5 mg/kg was longer in 12-day-old than in adult rats. This dose of Ro 19-8022 resulted in a rebound proconvulsant effect 24 and 48 h after the administration in 12-day-old rats only. Ro 19-8022 exhibited an excellent anticonvulsant action especially against generalized tonic-clonic seizures; this action was lost with very high doses. It did not compromise the motor system, but in some tests motivation was probably lost.
Kubová
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H
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague. kubova@biomed.cas.cz
Mikulecká
A
A
Haugvicová
R
R
Mares
P
P
D000375:Aging; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D058787:GABA-A Receptor Antagonists; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009048:Motor Skills / Q000187:drug effects*; D010433:Pentylenetetrazole; D011759:Pyrrolidines / Q000494:pharmacology* / Q000633:toxicity; D011807:Quinolizines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
D000927:Anticonvulsants; D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D011759:Pyrrolidines; D011807:Quinolizines; C076809:Ro 19-8022; D008874:Midazolam; D010433:Pentylenetetrazole