Histamine H1 receptor-mediated inhibition of potassium-evoked release of 5-hydroxytryptamine from mouse forebrains.

The release of endogenous serotonin and dopamine from slices of mouse forebrains induced by high extracellular K(+) was examined in histamine H1 receptor knockout mice. The release of 5-hydroxytryptamine (5-HT) evoked by 30 mM K(+) significantly decreased in the presence of 10-50 microM histamine in wild-type mice, but was not inhibited in the mutant mice. Histamine H1 receptor-mediated inhibition of serotonin release in wild-type mice was also observed in the presence of thioperamide, an H3 antagonist. From these data, we postulate that endogenous histamine indirectly inhibits the release of 5-HT through H1 receptors in addition to H3 receptors. The treatment of 2 microM tetrodotoxin could partly abolish the effects of histamine on K(+)-evoked 5-HT release. Bicuculline, a GABA(A) antagonist, could reverse the histamine-induced inhibition of 5-HT release in wild-type mice, suggesting that H1 receptors facilitate the release of GABA, which in turn inhibits 5-HT release through GABA(A) receptors. The difference in the effects of d- and l-chlorpheniramine on K(+)-evoked 5-HT release in wild-type mice further supports the evidence of the function of H1 receptor modulating 5-HT release.