Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121

Michael Olive, Wesley F. Seidel, Dale M. Edgar

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 nonrapid 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.

Original languageEnglish (US)
Pages (from-to)1073-1083
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume285
Issue number3
StatePublished - Jun 1998
Externally publishedYes

Fingerprint

Autoreceptors
Dopamine Antagonists
Wakefulness
Sleep
Eye Movements
Locomotion
Disorders of Excessive Somnolence
REM Sleep
Body Temperature
Wakefulness-Promoting Agents
Light
Methylcellulose
Sleep Deprivation
Photoperiod
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121. / Olive, Michael; Seidel, Wesley F.; Edgar, Dale M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 285, No. 3, 06.1998, p. 1073-1083.

Research output: Contribution to journalArticle

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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 nonrapid 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.",
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