Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women

Abstract

Objective Since longitudinal studies determined that anxiety is a strong risk factor for hot flashes, we hypothesized that an anxiogenic stimulus that signals air hunger (hypercapnic, normoxic gas) would trigger an exacerbated hot flash-associated increase in tail skin temperature (TST) in a rat ovariectomy (OVEX) model of surgical menopause and hot flashes in symptomatic menopausal women. We also assessed TST responses in OVEX serotonin transporter (SERT)+/− rats that models a common polymorphism that is associated with increased climacteric symptoms in menopausal women and increases in anxiety traits. Methods OVEX and sham-OVEX rats (initial experiment) and wildtype and SERT+/− OVEX rats (subsequent experiment) were exposed to a 5 min infusion of 20%CO2 normoxic gas while measuring TST. Menopausal women were given brief 20% and 35%CO2 challenges, and hot flashes were self-reported and objectively verified. Results Compared to controls, OVEX rats had exacerbated increases in TST, and SERT+/− OVEX rats had prolonged TST increases following CO2. Most women reported mild/moderate hot flashes after CO2 challenges, and the hot flash severity to CO2 was positively correlated with daily hot flash frequency. Conclusions The studies demonstrate that this anxiogenic stimulus is capable of inducing cutaneous vasomotor responses in OVEX rats, and eliciting hot flashes in menopausal women. In rats, the severity of the response was mediated by loss of ovarian function and increased anxiety traits (SERT+/−), and, in women, by daily hot flash frequency. These findings may provide insights into anxiety related triggers and genetic risk factors for hot flashes in thermoneutral environments.

A Neural Circuit Underlying the Generation of Hot Flushes

“…This pulsatile activity pattern, however, is not sufficient to explain the sporadic, episodic nature of hot flushes. Epidemiological data indicate that numerous sensory and interoceptive cues can evoke flushing in menopausal women, including: higher ambient temperature, consumption of spicy foods, anxiety, altitude, and acute physiological stressors (Federici et al, 2016; Hunter et al, 2013; Swartzman et al, 1990). Thus, we hypothesize that flushes occur when excitatory external cues converge on Kiss1 ARH neurons during an episode of endogenous activity.…”

Estrogen replacement attenuates stress-induced pressor responses through vasorelaxation via β2-adrenoceptors in peripheral arteries of ovariectomized rats

“…This study was undertaken to elucidate whether chronic estrogen replacement attenuates psychological stress-induced pressor responses by suppressing peripheral vasoconstriction through ␤ 2 -AR activation in ovariectomized rats. Although younger than appropriate for a postmenopausal model, the ovariectomized rat is an animal model widely used for studying the pathology of human menopause (4,5,12). We examined the effects of estrogen under physiological and noncyclical concentrations in 17␤-estradiol (E 2 )-replaced rats on the stressinduced pressor response, as would be seen in a postmenopausal model with replacement by E 2 or in proestrus rats.…”

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression

“…The decrease in E 2 level and an increase in FSH level together with longer residence time at the corner by open field test caused by the removals of rat ovaries and stimulation by CUMS in this study were the key symptoms for PD (Salazar-Pousada et al, 2017). Many other perimenopausal animal models were applied: hot flash animal models of menopausal women (Federici et al, 2016); the loss of ovarian small follicles and intact ovaries caused by the occupational chemical 4-vinylcyclohexene diepoxide could induce a perimenopause stage in rats (Brooks et al, 2016) and so on. In this study, complete deletion of left ovary and 80% deletion of right ovary were performed to induce perimenopausal model, which led to a sharp decrease in E 2 .…”