Early life stress and hormonal status influence orexin-1 receptor expression in structures regulating cardiorespiratory responses to CO2.

Excessive cardiorespiratory responses to CO2 are a hallmark of panic disorder (PD). Female sex and exposure to early life stress are risk factors for PD. Neonatal maternal separation (NMS; 3 h/day, postnatal days 3-12) augments the ventilatory response to CO2 by ∼35% relative to controls; this effect is most notable during pro-oestrus but is not observed in males. Orexin-1 receptor (OX1-R) antagonism attenuates the CO2 response of NMS females. In the limbic system, stress and ovarian hormones influence OX1-R expression, but the impact of these factors on OX1-Rs in regions regulating the cardiorespiratory responses to CO2 is unknown. Here, we hypothesised that ovarian hormones and NMS determine OX1-R expression in structures regulating the CO2 response; we used in situ hybridisation to quantify OX-1R mRNA expression in the brains of adult NMS and control rats. Brains were harvested from females that were either in pro-oestrus (high ovarian hormones) or 2 weeks post ovariectomy (OVX; low ovarian hormones); males were included for comparison. Hormonal status influenced the intensity of the OX1-R signal in the medial amygdala, raphe obscurus (RObs) and the A5 area, but the direction of the changes (increase vs. decrease) was structure-specific. Significant NMS × hormonal status interactions were noted in the dorsal raphe, the locus coeruleus, the nucleus of the solitary tract and the A5 area; the effects were structure-specific. As the dorsal raphe was the only structure in which the changes in OX1-R expression matched the sex-specific effect of NMS on the CO2 response, this structure likely contributes to respiratory manifestations of PD.