α-Dendrotoxin (α-DTX) is a 59 amino acid polypeptide isolated from the eastern green mamba (Dendroaspis angusticeps) snake venom which blocks certain types of fast-activating, voltage-dependent potassium channels. Intracerebral injection of α-DTX induces severe seizures and neuropathological changes in several areas of the brain, as shown by benzodiazepine ω 3 binding-site measurements (Lallement et al., unpublished). In order to gain an insight into these effects of α-DTX, we have studied the effect of the toxin on the release of the excitatory neurotransmitters acetylcholine (ACh) and glutamate (Glu) in the rat hippocampus. Microdialysis in area CA1 of freely moving rats failed to reveal any changes in extracellular levels of ACh and Glu after intracerebroventricular (i.c.y.) injection of α-DTX (20 pmoles). In vitro experiments on superfused hippocampal minislices were then carried out to determine the effect of α-DTX on the basal release of radiolabelled or endogenous neurotransmitters. α-DTX (1 μM) increased the basal efflux of labelled ACh and Glu and of endogenous Glu and GABA. This increase in release was not prevented by the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 300 or 500 μM). In contrast, extracellular recordings from hippocampal slices showed that the epileptiform activity induced by α-DTX (250 nM) was blocked by DNQX (10 μM), but not by the NMDA receptor antagonist d,l-2-amino-5-phosphonopentanoic acid (AP5, 100 μM). We conclude that DNQX blocks α-DTX-induced seizures by antagonism of postsynaptic non-NMDA receptors.