SEIZURES AND BRAIN INJURY IN NEONATAL RATS INDUCED BY 1S,3R-ACPD, A METABOTROPIC GLUTAMATE-RECEPTOR AGONIST

The role of metabotropic excitatory amino acid receptors in seizures a nd brain injury was examined using the selective metabotropic agonist 1 S,3R-ACPD [(l S,3R)- 1 -aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Systemic administration of 1 S,3R-ACPD produced dose-dependent convulsions (ED50 = 16 mg/kg, i.p.) that were stereose lective for the active metabotropic ACPD isomer, since 1R,3S-ACPD was less potent (ED50 = 93 mg/kg, i.p.). 1 S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrolene, an inhibitor of intracellular calcium mobilization, but not by the ionotropic glutama te antagonists MK-801 or GYKI-52466. As indexed by hemispheric brain w eight differences 5 d postinjection, unilateral intrastriatal injectio n of 1S,3R-ACPD (0.1-2.0 mumol/mul), but not 1 R,3S-ACPD, produced dos e-dependent brain injury (maximal effect of 3.4 +/- 0.5% damage). 1 S, 3R-ACPD brain injury occurred in the absence of prominent behavioral c onvulsions. Histologic and ultrastructural examination of 1 S,3R-ACPD- injected rat brains revealed swelling and degeneration of select neuro ns at 4 hr postinjection, but little evidence of injured neurons 5 d l ater. 1 S,3R-ACPD-mediated brain injury was not attenuated by systemic administration of the NMDA antagonist MK-801 or the AMPA antagonist G YKI-52466. However, cointrastriatal injection of dantrolene reduced th e severity of 1S,3R-ACPD injury by 88 +/- 7%. These studies indicate t hat seizures and neuronal injury can be elicited by the selective acti vation of metabotropic glutamate receptors in perinatal rats, and thes e effects of 1 S,3R-ACPD involve the mobilization of intracellular cal cium stores.