Effects of hypomagnesia on histamine H1 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 microM) reversibly facilitated the NMDA-induced depolarization yielding a bellshaped concentration-response relationship. The peak enhancement was 167% above the control at 10 microM 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 microM 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 microM) facilitated the NMDA (25 microM)-induced depolarization in nominally Mg(2+)-free medium. The magnitude of the facilitation was smaller than that observed in Mg(2+)-containing medium (17% above the control) and desensitization was not observed. This facilitation was not reduced by cyproheptadine (10 nM) or diphenhydramine (1 microM). 6. We conclude that histamine facilitates the NMDA depolarization at cortical neurones via two distinct mechanisms. One mechanism involves activation of the histamine H1 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.