Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current.

Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.