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

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. Histamine (1 to 15 μ M ) reversibly facilitated the NMDA‐induced depolarization yielding a bell‐shaped concentration‐response relationship. The peak enhancement was 167% above the control at 10 μ M histamine. Desensitization was present in 4 out of 5 slices on second exposure 40 min following the first exposure. Histamine did not alter the depolarization induced by 10 μ M kainate. The histamine‐induced facilitation persisted in the presence of tetrodotoxin, but was reduced in a concentration‐dependent manner by diphenhydramine (IC 50 =7.6 n M ). Cyproheptadine (10 n M ) also reduced the facilitation, whereas ranitidine (200 n M ) and thioperamide (10 n M ) were ineffective in this regard. Histamine (10 μ M ) facilitated the NMDA (25 μ M )‐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 n M ) or diphenhydramine (1 μ M ). 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 Mg 2+ . The second mechanism is independent of histamine cell surface receptor activation and may reflect a direct action of histamine at the NMDA receptor.British Journal of Pharmacology (1997) 121 , 199–204; doi: 10.1038/sj.bjp.0701123