Age-dependent anticonvulsant action of antagonists of group I glutamate metabotropic receptors in rats

Metabotropic glutamate receptors (mGluR) may represent a perspective target for anticonvulsant therapy but spectrum of their anticonvulsant effects is not sufficiently known. Our study was aimed at comparison of anticonvulsant actions of antagonists of mGluR1 and mGluR5 subtypes in immature rats. Seven-, 12-, 18- and 25-day-old animals were pretreated with mGluR1 antagonist AIDA (1-20 mg/kg i.p.) or mGluR5 antagonist MTEP (5-40 mg/kg i.p.) 30 min before pentetrazol administration (100 mg/kg s.c.). Two types of motor seizures were elicited: minimal, clonic seizures (mS) and generalized tonic-clonic seizures (GTCS). mS could be induced only in 18- and 25-day-old rats, and their incidence was decreased to 0-50% by nearly all doses of either drug in 18- but not in 25-day-old rats. GTCS were observed in all age groups; higher doses of both antagonists specifically suppressed the tonic phase in 7-, 12-and 18-day-old rats. The highest efficacy was found in 12-day-old rats; seizure severity was significantly decreased even by the 10-mg/kg dose of MTEP and the 2-mg/kg dose of AIDA in this age group. In addition, MTEP tended to suppress also the clonic phase in 7-day-old rats. Time course of action studied in 12-day-old animals demonstrated much longer action of MTEP (more than 4h) than of AIDA (less than 1 h). Administration of AIDA but not MTEP resulted in a paradoxical shortening of latencies of seizures even at time intervals when the incidence of the tonic phase of GTCS was decreased. Both mGluR antagonists exhibit specific anticonvulsant action in rat pups during the first 3 postnatal weeks. (C) 2008 Elsevier B.V. All rights reserved.