Monoaminergic system lesions increase post-sigh respiratory pattern disturbance during sleep in rats

Abstract

Monoamines are important regulators of behavioral state and respiratory pattern, and the impact of monoaminergic control during sleep is of particular interest for the stability of breathing regulation. The aim of this study was to test the effects of systemically induced chemical lesions to noradrenergic and serotonergic efferent systems, on the expression of sleep-wake states, pontine wave activity, and sleep-related respiratory pattern and its variability. In chronically instrumented male adult Sprague-Dawley rats we lesioned noradrenergic terminal axonal branches by a single intraperitoneal dose of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-brombenzilamine; 50 mg/kg, i.p.), and serotonergic axonal terminals by two intraperitoneal doses, 24 h apart, of PCA (p-chloroamphetamine; 6 mg/kg, i.p.). In each animal, we recorded sleep, pontine waves (P-waves) and breathing at baseline, following sham injection, and every week for 5 weeks following injection of either systemic neurotoxin. Distinct responses were observed to the two lesions. DSP-4 lesions were associated with a trend toward increased NREM sleep (p < 0.06), decreased wakefulness (p < 0.05) and increased respiratory tidal volume during NREM (p = 0.0002) and REM (p = 0.0001) sleep with respect to baseline. None of these effects, however, were observed during the first 14 days after injection. No significant changes were observed in the frequency of apneas or sighs, nor in the coupling between these two, at any time after DSP-4 injection. Conversely, selective serotonergic lesion by PCA produced no change in the baseline respiratory frequency or tidal volume during sleep or wakefulness, nor was the expression of Wake, NREM or REM sleep affected. Instead, PCA injection resulted in a sustained increase in the frequency and duration of post-sigh apneas (PS) during NREM sleep (p = 0.002). This reflected increased coupling between sighs and apneas, because neither the frequency nor the amplitude of spontaneous sighs was altered by PCA.