Ionotropic histamine receptors and H2 receptors modulate supraoptic oxytocin neuronal excitability and dye coupling

Abstract

Histaminergic neurons of the tuberomammillary nucleus (TM) project monosynaptically to the supraoptic nucleus (SON). This projection remains intact in our hypothalamic slices and permits investigation of both brief synaptic responses and the effects of repetitively activating this pathway. SON oxytocin (OX) neurons respond to single TM stimuli with fast IPSPs, whose kinetics resemble those of GABAA or glycine receptors. IPSPs were blocked by the Cl- channel blocker picrotoxin, but not by bicuculline or strychnine, and by histamine H2, but not by H1 or H3 receptor antagonists, suggesting the presence of an ionotropic histamine receptor and the possible nonspecificity of currently used H2 antagonists. G-protein mediation of the IPSPs was ruled out using guanosine 5′-O-(2-thiodiphosphate) (GDP-βS), pertussis toxin, and Rp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (Rp-cAMPs), none of which blocked evoked IPSPs. We also investigated the effects of synaptically released histamine on dye coupling and neuronal excitability. One hundred seventy-three OX neurons were Lucifer yellow-injected in horizontal slices. Repetitive TM stimulation (10 Hz, 5-10 min) reduced coupling, an effect blocked by H2, but not by H1 or H3, receptor antagonists. Because H2 receptors are linked to activation of adenylyl cyclase, TM-stimulated reduction in coupling was blocked by GDP-βS, pertussis toxin, and Rp-cAMPs and was mimicked by 8-bromo-cAMP, 3-isobutyl-1-methylxanthine, and Sp-cAMP. Membrane potentials of OX and vasopressin neurons were hyperpolarized, accompanied by decreased conductances, in response to bath application of 8-bromo-cAMP but not the membrane-impermeable cAMP. These results suggest that synaptically released histamine, in addition to evoking fast IPSPs in OX cells, mediates a prolonged decrease in excitability and uncoupling of the neurons.