The mGlu(2/3) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate, is anti-and proconvulsant in DBA/2 mice

The anticonvulsant activity of the selective group II metabotropic glutamat e receptor (mGlu) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R -APDC) has been evaluated in chemoconvulsant and sound-induced models of ep ileptic seizures in DBA/2 mice. 2R,4R-APDC(greater than or equal to 10 nmol , intracerebroventricularly (i.c.v.), -15 min) transiently reduced sound-in duced seizure activity including clonic seizures to 40% of vehicle at 20 nm ol (i.c.v.) and 30% of vehicle at 100 mg/kg (intraperitoneally (i.p,), -15 min). 2R,4R-APDC inhibited clonic seizures induced by the group III mGlu an tagonist (R,S)-alpha -methylserine-O-phosphate (2.5 mu mol, i.c.v.) when co -injected at 20-40 nmol and inhibited limbic seizure activity induced by th e mGlu(1/5) agonist (R,S)-3,5-dihydroxyphenylglycine (1.5 mu mol, i.c.v.) w hen co-injected at 10-40 nmol. A reversal of the anticonvulsant activity of 2R,4R-APDC was observed at (>20 nmol) in each of the chemoconvulsant and s ound-induced models of epileptic seizures. 2R,4R-APDC (0.1-1 mu mol, i.c.v. ) induced stimulus-independent, rapid and dose-dependent clonic seizures. S elective mGlu(2/3) agonists represent a novel class of potential anti-epile ptic drugs, however due to the proconvulsant activity observed here, 2R,4R- APDC is obviously limited in this regard. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.