Impact of acute fluoxetine (FLX) administration on inspiratory motor activity response to acute hypoxic‐hypercapnic exposure in urethane‐anesthetized spontaneously breathing female rats at 24‐hr post‐lipopolysaccharide (LPS) injection

Abstract

In the respiratory neural control system, LPS‐induced neuroinflammation has been shown to affect multiple aspects of central ventilatory control, including 5‐HT‐dependent inspiratory motor behaviors. LPS‐induced neuroinflammation can alter serotonergic (5‐HT) neurotransmission by acting on the serotonin transporter to alter serotonin levels, which could subsequently contribute to ventilatory deficits noted in LPS‐induced neuroinflammation. Ongoing work in our laboratory has begun to assess this possibility, and we recently found that acute systemic administration of the SSRI fluoxetine hydrochloride (FLX) is capable of restoring the maximal chemoreceptor stimulation ventilatory response (MCVR) elicited by an acute single bout of combined hypoxic‐hypercapnic exposure in spontaneously breathing urethane‐anesthetized adult male Sprague‐Dawley rats 24‐hr after systemic LPS. Since estrogens can exert anti‐inflammatory and neuroprotective effects that have the capacity to influence multiple aspects of the inflammatory process, it remains to be determined whether similar observations would be noted in female rats. Therefore, we have conducted additional experiments to evaluate the effects of acute systemic FLX administration on the MCVR in spontaneously breathing urethane‐anesthetized adult female Sprague‐Dawley rats 24‐hr after systemic administration of LPS (3 mg/kg, ip) or vehicle (0.9% saline, ip) delivered during proestrus (high estrogen) or diestrus (low estrogen). For these experiments, basal diaphragm EMG activity was recorded for 30 min under baseline (BL) conditions (40% O2), FLX (10 mg/kg, iv) was then administered and allowed to exert its effects for 30 min, after which a 3 min MCVR (12% O2, 7%CO2) challenge was performed, followed by 30 min recovery. We found that in both LPS‐ and vehicle‐treated rats, acute FLX administration produced an initial brief tonic discharge in EMG activity (which was not observed in male rats) that was followed by a transient increase in both burst frequency and amplitude that recovered to BL levels prior to the MCVR challenge. In post‐LPS‐ and vehicle‐treated proestrus rats and vehicle‐treated diestrus rats, there was a sustained robust increase in burst frequency and amplitude during the MCVR challenge. In post‐LPS‐treated diestrus rats, a slightly blunted but sustained MCVR‐induced increase in burst frequency behavior was noted; however, the increase in burst amplitude rapidly waned and returned to BL levels before the end of the MCVR challenge. These preliminary observations suggest that acute FLX administration following LPS administration delivered to female rats during diestrus is unable to restore inspiratory motor deficits in hypoxic‐hypercapnic chemical control of breathing. This is in contrast to our prior findings in LPS‐treated male rats and differs from our observations in proestrus LPS‐treated female rats, and may be interpreted to suggest that hormonal changes associated with the estrous cycle can strongly influence LPS‐induced inflammation‐mediated alterations in ventilatory control.Support or Funding InformationNIH NS101737