Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO(2) inhalation in a female rat model of panic disorder

Panic disorder (PD) is ~2 times more frequent in women. An excessive ventilatory response to CO(2) inhalation is more likely during the premenstrual phase. While ovarian hormones appear important in the pathophysiology of PD, their role remains poorly understood as female animals are rarely used in pre-clinical studies. Using neonatal maternal separation (NMS) to induce a “PD-like” respiratory phenotype, we tested the hypothesis that NMS disrupts hormonal regulation of the ventilatory response to CO(2) in female rats. We then determined whether NMS attenuates the inhibitory actions of 17-β estradiol (E(2)) on orexin neurons (ORX). Pups were exposed to NMS (3 h/day; postnatal day 3–12). The ventilatory response to CO(2)-inhalation was tested before puberty, across the estrus cycle, and following ovariectomy. Plasma E(2) and hypothalamic ORX(A) were measured. The effect of an ORX(1) antagonist (SB334867; 15 mg/kg) on the CO(2) response was tested. Excitatory postsynaptic currents (EPSCs) were recorded from ORX neurons using whole-cell patch-clamp. NMS-related increase in the CO(2) response was observed only when ovaries were functional; the largest ventilation was observed during proestrus. SB334867 blocked this effect. NMS augmented levels of ORX(A) in hypothalamus extracts. EPSC frequency varied according to basal plasma E(2) levels across the estrus cycle in controls but not NMS. NMS reproduces developmental and cyclic changes of respiratory manifestations of PD. NMS disrupts the inhibitory actions of E(2) on the respiratory network. Impaired E(2)-related inhibition of ORX neurons during proestrus is a novel mechanism in respiratory manifestations of PD in females.