MECHANISMS OF ANTIHISTAMINE-INDUCED SEDATION IN THE HUMAN BRAIN - H-1 RECEPTOR ACTIVATION REDUCES A BACKGROUND LEAKAGE POTASSIUM CURRENT

Antihistamines, more formally termed H-1 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 mu M 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 H-1 antagonist mepyramine, but not by the H-2 antagonist cimetidine nor the H-3 antagonist thioperamide. The H-3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H-1 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 H-1 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 H-1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H-1 receptors by systemically administered H-1 receptor antagonists would be sedating.