ABSTRACT
Histaminergic neurons of the tuberomammillary nucleus (TMN) are pH sensitive and contribute to CO2/H+-dependent behaviors including arousal and respiratory activity. TMN neurons project to several respiratory centers including the ventral parafacial region (pF), where the chemosensitive retrotrapezoid (RTN) neurons are located, and since RTN neurons are an important source of CO2/H+-dependent respiratory drive, we wondered whether histamine contributes to RTN chemoreception. To test this, we characterized effects of histamine on mean arterial pressure (MAP) and diaphragm muscle activity (DIAEMG) in urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Unilateral injection of histamine in the pF (25 mM) increased DIAEMG amplitude without changing DIAEMG frequency and MAP. Bilateral injections of the H1 receptor antagonist diphenhydramine hydrochloride (DPH; 0.5 mM) into the pF decreased baseline DIAEMG amplitude and frequency and MAP. Despite the strong inhibitory effect of DPH on baseline breathing, the hypercapnic ventilatory response was preserved under these experimental conditions. At the cellular level, chemosensitive RTN neurons showed a dose-dependent excitatory response to histamine that was blunted by DPH and mimicked by H1 receptor agonist 2-pyridylethylamine dihydrochloride (2PYEA) both under control conditions and when fast neurotransmitter receptors were blocked. We also tested effects of 2PYEA in the presence of serotonin, another wake-on neurotransmitter that activates RTN chemoreceptors partly by activation of Gq-coupled receptors. We found that the response to 2PYEA was diminished in serotonin, suggesting that RTN neurons have a limited capacity to respond to multiple Gq-coupled modulators. These results suggest that histamine can modulate breathing at the pF level by a mechanism involving H1 receptors.NEW & NOTEWORTHY Histamine/H1 receptor signaling activates retrotrapezoid (RTN) neurons under control conditions and to a lesser extent in the presence of serotonin. These results suggest that RTN neurons have a limited capacity to respond to simultaneous activation of multiple Gq-coupled receptors.