SPECIFIC GROUP-II METABOTROPIC GLUTAMATE-RECEPTOR ACTIVATION INHIBITSTHE DEVELOPMENT OF KINDLED EPILEPSY IN RATS

The effects of intracerebral administration of the group II metabotrop ic glutamate receptor agonist, 2R,4R-APDC, were tested on both the dev elopment of amygdaloid kindling and on fully developed stage 5 amygdal a kindled seizures. The development of amygdaloid kindling was signifi cantly retarded in 2R,4R-APDC (10 nmol in 0.5 mu l) treated animals co mpared to control animals over a period of 8 days. At a low dose, 2R,4 R-APDC (0.1 nmol) caused a 42.5 +/- 26.6% increase of the generalised seizure threshold in fully kindled animals. As higher doses were admin istered, however, the changes in generalised seizure threshold were le ss marked, and even a small decrease in the threshold was seen (-19.6 +/- 5.36% at 10 nmol). The agonist 2R,4R-APDC inhibited depolarization -induced release of [H-3]D-aspartate from cortical synaptosomes with a n IC50 value of 0.29 mu M. This effect was maximal at 1 mu M, and decr eased with dose thereafter. These findings suggest that the selective activation of the group II metabotropic glutamate receptors by agonist s such as 2R,4R-APDC may be of therapeutic potential in the treatment of seizure disorders. (C) 1998 Elsevier Science B.V.