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Histamine-Induced Excitatory Responses in Mouse Ventromedial Hypothalamic Neurons: Ionic Mechanisms and Estrogenic Regulation

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, New York

Submitted 26 March 2007; accepted in final form 12 October 2007

Histamine is capable of modulating CNS arousal states by regulating neuronal excitability. In the current study, histamine action in the ventromedial hypothalamus (VMH), its related ionic mechanisms, and its possible facilitation by estrogen were investigated using whole cell patch-clamp recording in brain slices from ovariectomized female mice. Under current clamp, a bath application of histamine (20 µM) caused membrane depolarization, associated with an increased membrane resistance. In some cells, the depolarization was accompanied by action potentials. Histamine application also significantly reduced the latency of action potential evoked by current steps. Histamine-induced depolarization was not affected by either tetrodotoxin or Cd²⁺. However, after blocking K⁺ channels with tetraethylammonium, 4-aminopyridine, and Cs⁺, depolarization was significantly decreased. Under voltage clamp, histamine-induced depolarization was associated with an inward current. The current–voltage relationship revealed that this inward current reversed near E_K. The histamine effect was mimicked by a histamine receptor 1 (H₁) agonist, but not a histamine receptor 2 (H₂) agonist. An H₁ antagonist, but not H₂ antagonist, abolished histamine responses. When ovariectomized mice were treated with estradiol benzoate (E2), histamine-induced depolarization was significantly enhanced with an increased percentage of cells showing action potential firing. These results suggest that histamine depolarized VMH neurons by attenuating a K⁺ leakage current and this effect was mediated by H₁ receptor. E2 facilitated histamine-induced excitation of VMH neurons. This histamine effect may present a potential mechanism by which estrogens modulate the impact of generalized CNS arousal on a sexual arousal–related neuronal group.

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