INDUCTION OR PROTECTION OF LIMBIC SEIZURES IN MICE BY MGLUR SUBTYPE-SELECTIVE AGONISTS

The behavioral consequences of metabotropic glutamate receptor (mGluR) activation were investigated following intracerebral administration o f the mGluR selective agonists (RS)3,5-dihydroxyphenylglycine (3,5-DHP G), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), (1R,3S )-1-aminocyclopentane-1 ,3-dicarboxylate (1R,3S-ACPD), L-2-amino-4-pho sphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP) and (2S,3S,4S)alp ha-(carboxycyclopropyl)glycine (L-CCGI) into the thalamus in mice. Inj ections of 3,5-DHPG, 1S,3R-ACPD and L-CCGI produced dose-dependent inc reases in limbic seizures with a potency order of 3,5-DHPG = 1S,3R-ACP D > L-CCGI. This effect of 1S,3R-ACPD was stereoselective, since the i nactive isomer (1R,3S-ACPD) did not elicit seizure activity. Limbic se izures induced by the phosphoinositide-coupled mGluR subtype selective agonist 3,5-DHPG were attenuated by the mGluR antagonist L-2-amino-3- phosphonopropanoic acid (L-AP3) and dantrolene, inhibitors of mGluR-me diated intracellular calcium mobilization. Interestingly, L-AP4, L-SOP and low doses of L-CCGI also protected against 3,5-DHPG seizures. The se data indicate that mGluR agonist-induced limbic seizures in mice ar e mediated by activation of phosphoinositide-coupled mGluRs. Furthermo re, these seizures can be protected against by activation of mGluRs th at are negatively-linked to cAMP formation.