Improved Acute Hypoxic Ventilatory Response (HVR) After Pharmacological Activation of 5‐HT1A Receptors in Two‐Hit Lipopolysaccharide (LPS)‐Treated Urethane‐anesthetized Spontaneously Breathing Adult Male Sprague‐Dawley Rat with Prior Single‐Bout Acute Intermittent Hypoxia Exposure

Abstract

Accumulating evidence indicates that inflammation and serotonergic (5‐HT) neurotransmission interact thereby affecting a variety of physiological processes. Ongoing studies in our laboratory are examining the effects of peripheral inflammation, and its accompanying neuroinflammation, on the neural control of breathing, including the impact of LPS‐induced neuroinflammation on 5‐HT1A receptor‐mediated inspiratory motor behaviors. Here, we examined the effects of systemic administration of the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐npropylamino) tetralin (8‐OH DPAT) on the (diaphragm) EMG burst amplitude and frequency response to a single bout of acute hypoxia (HVR; 11% O2 for 90s) in spontaneously breathing urethane‐anesthetized adult male Sprague‐Dawley rats following a ‘two‐hit’ lipopolysaccharide (LPS) administration protocol in which systemic LPS (3 mg/kg, ip) was administered ~24 hr prior to an intratracheal LPS (0.5 mg/kg, IT) injection. Similar HVR experiments were performed in control rats that were either untreated or received two‐hit saline injections. All rats used for this study had also undergone an acute intermittent hypoxia (AIH) exposure protocol that was completed at least 90 min prior to administration of 8‐OH DPAT, and they were continuously supplied with 2% CO2 throughout the recording protocol. Following baseline (BL; 40% O2) recording of diaphragm EMG activity, 8‐OH DPAT (0.3 mg/kg, iv) was administered and allowed to exert its effects for 30 min, after which a 30s HVR challenge was performed (11% O2) followed by recovery under BL conditions. Data from these experiments were also compared to our previous observations in two‐hit LPS‐ and vehicle‐treated male rats that had not undergone an AIH exposure protocol or received 8‐OH DPAT (to serve as a control for two‐hit LPS HVR behaviors). In brief, we had reported that two‐hit LPS administration blunts the HVR amplitude response such that it increases by ≤10% above BL levels (versus ≥30% increase in vehicle‐treated rats) and produces an exaggerated frequency HVR response such that it increases by ≥30% above BL levels (versus~15–20% increase in vehicle‐treated rats). In contrast to these observations, in the current study, we found that following 8‐OH DPAT administration, the HVR exhibited similar increases in both burst frequency and amplitude in both control and LPS‐treated rats. In this case, HVR amplitude and frequency increased on average by ~23% and ~25%, respectively, although LPS‐treated rats exhibited variable magnitude HVR responses. Regardless, following 8‐OH DPAT administration, HVR inspiratory motor activity appeared to be indistinguishable between control and LPS‐treated rats. These observations suggest that following pharmacological activation of 5‐HT1A receptors, amplitude and frequency HVR behaviors are improved in two‐hit LPS‐treated rats. The specific mechanisms underlying these differences remain to be identified.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.