title: Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121.
abstract: 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.
authors.affiliation: Sleep Disorders and Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Olive
authors.forename: W F
authors.initials: WF
authors.lastname: Seidel
authors.forename: D M
authors.initials: DM
authors.lastname: Edgar
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012892:Sleep Deprivation / Q000502:physiology; D012895:Sleep, REM / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D009570:Nitriles; D010880:Piperidines; C094012:3-(3-cyanophenyl)-N-n-propylpiperidine