Effects of hypomagnesia on histamine H-1 receptor-mediated facilitation of NMDA responses

1 The ability of histamine to facilitate the N-methyl-D-aspartate (NMDA) induced depolarization of cortical projection neurones was examined by use of grease-gap recording. 2 Histamine (1 to 15 mu M) reversibly facilitated the NMDA-induced depolarization yielding a bell-shaped concentration-response relationship. The peak enhancement was 167% above the control at 10 mu M histamine. Desensitization was present in 4 out of 5 slices on second exposure 40 min following the first exposure. 3 Histamine did not alter the depolarization induced by 10 mu M kainate. 4 The histamine-induced facilitation persisted in the presence of tetrodotoxin, but was reduced in a concentration-dependent manner by diphenhydramine (IC50=7.6 nM). Cyproheptadine (10 nM) also reduced the facilitation, whereas ranitidine (200 nM) and thioperamide (10 nM) were ineffective in this regard. 5 Histamine (10 mu M) facilitated the NMDA (25 mu M)-induced depolarization in nominally Mg2+-free medium. The magnitude of the facilitation was smaller than that observed in Mg2+-containing medium (17% above the control) and desensitization was not observed. This facilitation was not reduced by cyproheptadine (10 nM) or diphenhydramine (1 mu M). 6 We conclude that histamine facilitates the NMDA depolarization at cortical neurones via two distinct mechanisms. One mechanism involves activation of the histamine H-1 receptor and is sensitive to Mg2+. The second mechanism is independent of histamine cell surface receptor activation and may reflect a direct action of histamine at the NMDA receptor.