EFFECTS OF EXCITATORY AMINO-ACID ANTAGONISTS ON DENDROTOXIN-INDUCED INCREASES IN NEUROTRANSMITTER RELEASE AND EPILEPTIFORM BURSTING IN RAT HIPPOCAMPUS IN-VITRO

Alpha-dendrotoxin (alpha-DTx), a snake venom toxin which blocks severa l types of fast-activating voltage-dependent potassium channels, induc es limbic seizures and neuronal damage when injected into the brain, T he mechanisms underlying these convulsant and neuropathological action s are not fully understood, We have studied the effects of alpha-DTx o n neurotransmitter release and electrical activity in rat hippocampal brain slices and the role of excitatory amino acid receptors in mediat ing these actions of the toxin, alpha-DTx increased the basal release of acetylcholine, glutamate, aspartate, and GABA in a concentration-de pendent manner and induced epileptiform bursting in the CA1 and CA3 re gions of the slice, The increase in neurotransmitter release was evide nt during the first 4 min after toxin addition, whereas the bursting a ppeared after a concentration-dependent delay (20-40 min with 250 nM t oxin), The N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and MK -801 had no effect on the frequency or amplitude of dendrotoxin-induce d epileptiform bursts, but the non-NMDA antagonists CNQX and DNQX abol ished bursting in both CA1 and CA3 within 4-6 min, In contrast, the to xin-induced increases in neurotransmitter release were not blocked by DNQX, This study has demonstrated that, following exposure to alpha-DT x, there is a rapid increase in the release of neurotransmitters which precedes the onset of epileptiform bursting in the hippocampus. Since DNQX abolished the bursting but had no effect on the increase in neur otransmitter release, these results suggest that DNQX blocks alpha-DTx -induced epileptiform activity by antagonism of postsynaptic non-NMDA receptors. (C) British Crown copyright 1997/DERA-published with the pe rmission of the Controller of Her Majesty's Stationery Office.