Sleep/waking and EEG power spectrum effects of a nonselective serotonin (5-HT) antagonist and a selective 5-HT reuptake inhibitor given alone and in combination

Sleep/waking stages, electroencephalogram (EEG) power spectra and behavior were studied in rats for 8 hours following intraperitoneal administration of a nonselective serotonin (5-HT) antagonist (0.1 and 2.0 mg/kg methiothepin) and a selective 5-HT reuptake inhibitor (20 mg/kg zimeldine), given alone and in combination. Consistent with earlier studies, zimeldine gave a biphasic effect on sleep and waking. Waking was increased and slow wave sleep (SWS)-2 decreased initially, followed by an increase in SWS-2 in the second 2-hour period. Rapid eye movement (REM) sleep was reduced throughout the experiment. EEG power densities were generally reduced in the higher frequencies, but the effect differed somewhat in the different vigilance states and between the fronto-frontal and fronto-parietal EEG leads. Zimeldine did not change behavior. Methiothepin, at 0.1 mg/kg, gave only minor effects by itself, but it blocked the initial waking increase of zimeldine. So did 2.0 mg/kg methiothepin, but this dose markedly changed sleep/waking stages by itself: SWS-1 was profoundly increased, whereas waking, SWS-2 and REM sleep were reduced. Total SWS (TSWS) was markedly increased due to the SWS-1 increase. Because TSWS was increased while SWS-2 was decreased following 2.0 mg/kg methiothepin, it is concluded that spindle activity was facilitated, whereas slow wave activity was antagonized. Methiothepin, at 2.0 mg/kg, also markedly changed EEG power densities within TSWS and induced cataleptic behavior. It is concluded that the initial waking increase of zimeldine depends on simultaneous activation of several different 5-HT receptor subtypes. The other zimeldine effects were not consistently antagonized, thus the mechanisms behind these effects remain unclear.