A hypothalamo-midbrain-medullary pathway involved in the inhibition of the respiratory chemoreflex response induced by potassium cyanide in rodents

Abstract

Recent studies have demonstrated that a mild stimulation of the dorsomedian nucleus of the hypothalamus (DMH), a defense area, induces the inhibition of the carotid chemoreflex tachypnea. DMH activation reduces the cardiac chemoreflex response via the dorsolateral part of the periaqueductal grey matter (dlPAG) and serotonin receptors (5-HT₃ subtype) in the nucleus tractus solitarius (NTS). The objectives of this study were to assess whether dlPAG and subsequent NTS 5-HT₃ receptors are involved in chemoreflex tachypnea inhibition during mild activation of the DMH. For this purpose, peripheral chemoreflex was activated with potassium cyanide (KCN, 40 μg/rat, i.v.) during electrical and chemical minimal supra-threshold (mild) stimulation of the dlPAG or DMH. In both situations, changes in respiratory frequency (RF) following KCN administration were reduced. Moreover, pharmacological blockade of the dlPAG prevented DMH-induced KCN tachypnea inhibition. Activation of NTS 5-HT₃ receptors also reduced chemoreflex tachypnea in a dose-dependent manner. In addition, blockade of NTS 5-HT₃ receptors with granisetron (2.5 but not 1.25 mM), or the use of mice lacking the 5-HT_3a receptor (5-HT_3a KO), prevented dlPAG-induced KCN reductions in RF. A respiratory hypothalamo-midbrain-medullary pathway (HMM) therefore plays a crucial role in the inhibition of the hyperventilatory response to carotid chemoreflex.

Keywords: 5-HT(3) receptor; Carotid chemoreflex; Hypothalamus; Nucleus tractus solitarius; Respiratory responses.