Effects of hypomagnesia on histamine H₁ receptor-mediated facilitation of NMDA responses

Abstract

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 μM) reversibly facilitated the NMDA-induced depolarization yielding a bell-shaped concentration-response relationship. The peak enhancement was 167% above the control at 10 μM 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 μM 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 μM) facilitated the NMDA (25 μM)-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 μM).

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.

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