The effects of 5,7-dihydroxytryptamine-induced lesions of the ascending 5-hydroxytryptamine pathways on the sleep-wakefulness cycle

Abstract

Summary The role of ascending 5-hydroxytryptamine (5-HT) systems in sleep and waking in the rat was investigated by making fairly selective lesions of these systems with the neurotoxin 5,7-dihydroxytryptamine (5,7-HT). 5,7-HT (4 μg/4 μl) was injected bilaterally into the dorsomedial mesencephalic tegmentum close to the 5-HT pathways. Another group of rats was pretreated with chlorimipramine (25 mg/kg, i.p.) 10 min before they received the intracerebral injections of 5,7-HT. The controls received the vehicle only. The EEG and EMG were continuously recorded for 2–4 postoperative days in order to measure the time the animals spent awake and in different sleep stages. The EEG recordings exhibited both in the 5,7-HT group and in the chlorimipramine-5,7-HT group an increase in waking activity and a corresponding decrease in slow wave sleep 2 (SWS 2) characterized by continuous high voltage slow waves. The changes were significant during 3–4 postoperative days. Unspecific neuronal damage (nerve cell degeneration, glial reaction) was observed at the site of 5,7-HT and vehicle injection (0.6 mm × 1.0 mm and 0.4 mm × 0.6 mm, respectively) but not in the region of the raphe, where the main 5-HT bundle ascends. Accumulations of 5-HT and noradrenaline (NA) were observed in the ascending 5-HT and NA pathways, respectively. The uptake-retention of [ 3 H]5-HT and [ 3 H]NA in the cortical slices and hypothalamic homogenates, predicting the degree of degeneration of 5-HT or NA nerve terminals, was correlated to the different EEG states. When [ 3 H]5-HT uptake in the cortical slices was considered, a significant negative intraindividual correlation was obtained between [ 3 H]5-HT uptake and SWS 1 time. Furthermore, the amount of cortical 5-HT terminals was positively correlated with the time spent in SWS 2 and paradoxial sleep (PS). The studies on the uptake of [ 3 H]NA showed that the NA neurons were also affected by the 5,7-HT treatment. Unexpectedly, chlorimipramine was not found to protect the 5-HT nerve terminals from degeneration, whereas the NA terminals were protected. The present results give further support for the view that the ascending 5-HT neurons are important for the maintenance of SWS 2.