THE detection of histamine H2-receptor antagonists1,2 has provided fresh impetus to the investigation of central effects of histamine3–7 and its possible role as a neurotransmitter3,8–10. In the hypothalamus of rat and cat microelectrophoretically applied histamine excites a large number of cells. This action, which is unique to the hypothalamus, is not selectively antagonised by the H1-receptor antagonist mepyramine or by the H2-receptor antagonist metiamide8,9. In the cortex of the cat several H1-antagonists were tested but no specific action could be demonstrated11. We report now on a selective antagonism of metiamide against depressant actions of histamine in the cerebral cortex of cat and rat.