ENDOGENOUS EXCITATORY AMINO-ACID RELEASE FROM BRAIN-SLICES AND ASTROCYTE CULTURES EVOKED BY TRIMETHYLTIN AND OTHER NEUROTOXIC AGENTS

Trimethyltin (TMT) is a toxic alkyltin compound that is known to produ ce neuronal necrosis in the CNS. The present study examined the effect s of TMT on the release of excitatory amino acids (EAA) from cortical slices prepared from adult and aged (24 months old) rats. The calcium dependence of TMT-induced EAA efflux was evaluated and compared to oth er neurotoxic agents. The actions of TMT were also evaluated in an ast rocyte culture model to assess glial contributions to TMT-induced EAA efflux. TMT (10-1000 mu M) evoked a dose-related increase in GLU and A SP efflux during a 30 min incubation period and this efflux was sustai ned or slightly higher during a 15 min recovery period. TMT-stimulated GLU efflux was not altered in aged rats. TMT-induced GLU efflux was s ignificantly reduced by removing extracellular calcium and including 1 0 mu M EGTA in the incubation media. Calcium channel blockers (nifedip ine, verapamil, flunarizine, amiloride, neomycin) and MK-801 did not s ignificantly attenuate TMT-induced GLU efflux. Diltiazem (25 mu M) pro duced modest but inconsistent reductions in TMT-induced GLU efflux fro m brain slices, and significantly inhibited the leakage of lactate deh ydrogenase (LDH) from TMT-treated astrocyte cultures. TMT did not incr ease GLU efflux from glial cultures during a 30 min incubation period, but did significantly elevate GLU efflux during the 15 min recovery p eriod. TMT evoked the release of EAA by both calcium dependent and ind ependent mechanisms in brain slices. TMT at high concentrations also p roduced a delayed increase in glial GLU efflux. These studies suggest that excitotoxic mechanisms may contribute to TMT-induced neurotoxicit y.