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Histamine Activates Chemosensitive Neurons in the Retrotrapezoid Nucleus
Author(s) -
Milla Brenda,
Sobrinho Cleyton,
Soto Jaseph,
Takakura Ana,
Mulkey Daniel,
Moreira Thiago
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02765
Subject(s) - histaminergic , histamine , endocrinology , chemistry , antagonist , medicine , anesthesia , receptor
Histaminergic neurons of the posterior hypothalamic tuberomammillary nucleus (TMN) are pH‐sensitive and contribute to CO2/H+‐dependent behaviors including arousal and respiratory activity. Considering histaminergic neurons project to several brainstem respiratory centers including the retrotrapezoid nucleus (RTN), and since chemosensitive RTN neurons are an important source of CO 2 /H + ‐dependent respiratory drive, we wondered whether and how histamine contributes to RTN chemoreception at the cellular level and in anesthetized rats. In brain slices obtained from rat pups (7‐12 days old), chemosensitive RTN neurons were identified in cell‐attached voltage‐clamp mode by their characteristic firing response to CO 2 (≥ 0.8 Hz increase in activity in response to 10% CO 2 ) . We found that most chemosensitive RTN neurons showed a dose dependent increase in activity in response to bath application of histamine dihydrochloride (HD: 1‐25 μM). The increased activity of RTN neurons by HD (25 mM) was blunted by bath application of the H1 receptor antagonist DPH (diphenhydramine hydrochloride; 100 µM) (1.1 ± 0.1 Hz to ‐0.06 ± 0.2 Hz; n = 7) or the H2 receptor antagonist ranitidine (ranitidine hydrochloride; 10 µM) (1.0 ± 0.2 Hz to 0.3 ± 0.3 Hz; n = 5). At the whole animal level, we measured mean arterial pressure (MAP) and diaphragm muscle activity (DIA EMG ) in urethane‐anaesthetized, vagotomized and artificial ventilated male Wistar rats. Unilateral injection of HD (25 mM ‐ 50 nl) into the RTN increased DIA EMG amplitude (17.41 ± 3.8 vs. saline: 0.55 ± 1.9%) and DIA EMG frequency (4.72 ± 1.7 vs ‐1.8 ± 1.5) without changes MAP. Bilateral injections of DPH (0.5 mM) into the RTN decreased DIA EMG amplitude (‐62.6 ± 14.5. vs. saline: ‐1.1 ± 1.3%), DIA EMG frequency (‐66.4 ± 13.4 vs. saline: ‐1.5 ± 1.9%) and MAP (‐43.67 ± 8,4 vs. saline: ‐3.2 ± 1.7 mmHg). Despite the strong inhibitory effect of DPH on baseline breathing, the hypercapnic ventilatory response was preserved in urethane‐anesthetized rats under these experimental conditions. These results suggest histamine signaling via H1 and H2 receptors modulates activity of RTN neurons and respiratory activity.