COMPENSATORY SLEEP RESPONSES TO WAKEFULNESS INDUCED BY THE DOPAMINE AUTORECEPTOR ANTAGONIST (-)DS121

The effect of the dopamine autoreceptor antagonist (-)DS121 on wakeful ness, 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 gr oup received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT -ls). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomo tor activity and body temperature, and decreased both nonrapid eye mov ement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference las ted 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 significa nt compensatory sleep responses. In contrast, higher doses (5 and 10 m g/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-trea tment 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 a t 10 mg/kg. In contrast, equivalent wakefulness produced by sleep depr ivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) incre ased wakefulness without disproportionately increasing locomotor activ ity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is follow ed by hypersomnolence that is proportional to drug-induced wake-promot ing efficacy.