Monoaminergic system lesions increase post-sigh respiratory pattern disturbance during sleep in rats J. Saponjic a, ⁎ , M. Radulovacki b , D.W. Carley a,b,c a Department of Medicine, University of Illinois, Chicago, IL 60612, USA b Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA c Department of Medical-Surgical Nursing, University of Illinois, Chicago, IL 60612, USA Received 17 March 2006; received in revised form 2 August 2006; accepted 15 August 2006 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 b 0.06), decreased wakefulness ( p b 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. © 2006 Elsevier Inc. All rights reserved. Keywords: Post-sigh apnea; Respiratory pattern disturbance; Sleep; Lesion; Monoamines; DSP-4; PCA; Neurotoxin 1. Introduction Noradrenergic locus coeruleus (LC) neurons and serotonergic dorsal raphe (DR) neurons are connected reciprocally with cho- linergic neurons of the pedunculopontine tegmental nucleus/ laterodorsal tegmental nucleus (PPT/LDT). Inhibitory interac- tions among these regions are important in regulating their activity [1–5] and the reciprocal and opposite discharge patterns of monoaminergic and cholinergic neurons were originally pro- posed to underline the cyclic appearance of REM sleep [3–5]. Experimental data from rats and cats suggest that various REM-sleep features are executed by distinct cell-groups in the brainstem that are triggered and modulated by activation of cholinergic neurons within the PPT [6]. Stimulation of the PPT with glutamate microinjection, presumably including choliner- gic neurons, dose-dependently increases REM and wakefulness [7], and alters the breathing pattern [8–12], but local injection of 5-HT or NA does not appear to affect REM sleep [13]. We recently demonstrated anatomically distinct sites within the PPT that separately modulate P-wave activity and respiratory pattern Physiology & Behavior 90 (2007) 1 – 10 ⁎ Corresponding author. Section of Respiratory and Critical Care Medicine, Department of Medicine (MC 719), 840 South Wood Street, Chicago, IL 60612- 7323, USA. Tel.: +1 312 996 3573 or 312 413 8461; fax: +1 312 996 4665. E-mail address: jasnasap@uic.edu (J. Saponjic). 0031-9384/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2006.08.019