Possible roles of thromboxane A2 (TXA2) in the release mechanism of hippocampal noradrenaline (NA) were examined in vitro. Slices or crude synaptosomes prepared from the rat hippocampus were superfused with modified Krebs-Ringer solution. Application of 20 mM KCl for 5 min increased the release of NA from the slices, and this release was consistently reproduced. Application of U-46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha), a specific TXA2 mimetic, just before the second KCl (20 mM) stimulation decreased the KCl-evoked NA release in a concentration-dependent manner (10-100 microM). This U-46619 (50 microM)-induced inhibition of NA release was abolished by 10 microM SQ29548, a specific TXA2 receptor antagonist. In experiments with hippocampal crude synaptosomes, however, KCl (20 and 40 mM)-evoked release of NA was not attenuated by U-46619 (100 microM). Furthermore, the inhibitory effect of U-46619 (50 microM) in the sliced preparations was not modified by 100 microM (-)-bicuculline, a GABA(A)-receptor antagonist. The present results indicate that U-46619 inhibits the release of NA from the rat hippocampus by activation of TXA2 receptors. Activation of TXA2 receptors probably excites an unidentified but not GABAergic neuron system, thereby inhibiting the NA release from the rat hippocampus.