Vol. 285, Issue 3, 1073-1083, June 1998

Compensatory Sleep Responses to Wakefulness Induced by the Dopamine Autoreceptor Antagonist ()DS121¹

M. Foster Olive, Wesley F. Seidel and Dale M. Edgar

Sleep Disorders and Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California

The effect of the dopamine autoreceptor antagonist ()DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. ()DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. ()DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, ()DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of ()DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 ± 9.9 min) and 10 mg/kg (64.8 ± 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, ()DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that ()DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.