Previous studies have demonstrated that REM sleep suppression produced by the serotonin1 agonist eltoprazine (1 mg/kg b.i.d., administered i.p.) is followed by a dramatic rebound in REM sleep. In the present study, cats were treated with scopolamine (2 mg/kg b.i.d.) after 3 days of eltoprazine-induced REM sleep suppression. During scopolamine treatment, the percentage of REM sleep (9.9 +/- 3.5%) was well below baseline levels (13.7 +/- 1.6%; P < 0.05). Even after the 3-day scopolamine treatment ended, the subsequent REM sleep rebound after the combined eltoprazine-scopolamine treatment (16.8 +/- 2.8% REM sleep during 3-day rebound; P < 0.10 compared to baseline) was less than a third of the rebound normally seen after eltoprazine. These results provide evidence for the reciprocal relationship between acetylcholine and serotonin and suggest a new set-point model for the mechanism of REM sleep regulation and rebound.