Histamine H1-receptor modulation of inter-neuronal coupling among vasopressinergic neurons depends on nitric oxide synthase activation

Inter-neuronal coupling is a relatively recently documented property of a wide variety of cell groups in the mammalian central nervous system. For many of these groups there is evidence that the coupling can be modulated by synaptic inputs. Incidence of dye coupling among vasopressin (VP) neurons of the rat supraoptic nucleus (SON) has been shown to increase in response to either activation of histamine H(1)-receptors or to increased NO production. Both of these effects involve activation of cGMP-dependent pathways. We tested the hypothesis that activation of H(1)-receptors resulted in downstream activation of NO synthase, which then mediated the H(1)-receptor effects. Putative VP neurons were intracellularly recorded and dye-injected in horizontal slices of hypothalamus, in which monosynaptic connections from the tuberomammillary nucleus (TM) were intact and electrically stimulated. Single-pulse TM stimulation evoked EPSPs and repetitive stimulation resulted in a nearly 3-fold increase in coupling incidence over unstimulated slices. TM-stimulated increased coupling was completely blocked by inhibitors of NO synthase (L-NAME) or of soluble guanylyl cyclase (ODQ or methylene blue), or pyrilamine, suggesting that the H(1)-receptor is not directly linked to guanylyl cyclase. Addition of the NO precursor, L-arginine or the NO donor, SNP, in combination with TM stimulation produced increases in coupling that were not significantly larger than those seen with stimulation alone, supporting the idea that a common pathway was used. We conclude that H(1)-receptors activate NO synthase via G-protein-coupled pathways and that NO working though its receptor, induces the downstream cGMP-dependent processes that result in increased inter-neuronal coupling.