Metabotropic glutamate receptors as a target for anticonvulsant and anxiolytic action in immature rats.

Antagonists of group I of metabotropic glutamate receptors (mGluRs) exhibit anticonvulsant as well as anxiolytic action in adult rodents. Therefore, we started to study these effects in developing rats. Motor seizures induced by pentylenetetrazol (PTZ) and cortical epileptic afterdischarges (CxADs) elicited by electrical stimulation were used in immature rats. High doses of antagonists were needed to demonstrate anticonvulsant effects. Antagonist of mGluR1 AIDA [(R,S)-1-aminoindan-1,5-dicarboxylic acid] suppressed the tonic phase of PTZ-induced generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats, but not in 25-day-old rats. No significant effect of AIDA against CxADs was found. Antagonists of mGluR5-MPEP [2-methyl-6-(phenylethynyl)-pyridine] and MTEP [3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine] exhibited the same effect against PTZ-induced seizures as AIDA. In addition, they exhibited an anticonvulsant action against CxADs in 12- and 18-day-old rats. No drug compromised motor performance. Anxiolytic action of all three antagonists was demonstrated in light/dark box or in elevated plus maze tests. Homing reaction was used as an age-appropriate test of learning. AIDA did not affect homing, whereas the highest dose of MPEP compromised this behavior in 12- and partially in 18-day-old rats. The three antagonists possess age-dependent anticonvulsant as well as anxiolytic action, with minimal negative side effects.

Antagonists of group I metabotropic glutamate receptors and cortical afterdischarges in immature rats.

PURPOSE: Antagonists of group I metabotropic glutamate receptors (mGluRs) are known to exhibit anticonvulsant action without serious side effects. Recently we found anticonvulsant effects of specific antagonists of mGluR subtypes 1 and 5 (AIDA and MTEP) against pentetrazol-induced convulsions in developing rats. In order to determine if the effects of these two antagonists are not exclusively restricted to pentetrazol-induced seizures, we studied their action in a novel seizure model involving immature rats. METHODS: Epileptic afterdischarges were elicited by low-frequency stimulation of sensorimotor cortical region in 12-, 18-, and 25-day-old rats with implanted electrodes. Drugs were administered intraperitoneally after the first afterdischarge: AIDA in doses from 5 to 40 mg/kg; MTEP in doses from 2.5 to 40 mg/kg. The stimulation was then repeated five more times with the same current intensity. Electrocorticographic and motor phenomena were recorded and evaluated. RESULTS: AIDA did not significantly influence movements during stimulation, afterdischarges as well as clonic seizures accompanying afterdischarges. In contrast, MTEP was able to significantly shorten afterdischarges without changes in the two motor phenomena. The effect of MTEP was best expressed in 12-day-old rats; in 25-day-old rats the trials exhibited only a transient shortening of afterdischarges after high doses of MTEP. DISCUSSION: In contrast to similar action against pentetrazol-induced seizures, AIDA and MTEP substantially differ in their action on cortical epileptic afterdischarges. The anticonvulsant action of MTEP in the present model diminishes with age.