The effects of brief anoxic episodes on intracellularly recorded CA3 pyramidal neurons have been studied in the hippocampal slice preparation. Anoxia induced a depolarization occasionally preceded by a transient hyperpolarization associated with a fall in input resistance. The anoxic depolarization was due to the release of glutamate from presynaptic terminals since it was blocked by tetrodotoxin (TTX) (1 microM) or by the broad spectrum excitatory amino acid antagonist kynurenate (1 mM). In the presence of TTX (1 microM) or kynurenate (1 mM), anoxia only induced a hyperpolarization which was due to activation of a K+ conductance. The anoxic depolarization was blocked by galanin, a hormone which activates ATP sensitive K+ (K+ATP) channels. Anoxic depolarization was increased by the potent sulfonylurea agent glibenclamide (GLIB) which blocks K+ATP channels. Bath applications of these agents had little effect when applied in oxygenated Krebs solution suggesting that their action may be mediated by K+ATP channels. Since excessive release of glutamate during anoxia is neurotoxic, agents such as galanin which activate K+ATP channels may provide tissue specific protection against anoxic damage.