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.
Footnotes
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Send reprint requests to: Dale M. Edgar, Ph.D., Sleep and Circadian Neurobiology Laboratory, Sleep Research Center, Stanford University School of Medicine, 701 Welch Road, Suite 2226, Palo Alto, CA 94304.
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↵1 Research supported by AG11084, AFOSR grant F49620–95-1–0388 and a grant from the Upjohn Company.
- Abbreviations:
- ANOVA
- analysis of variance
- AP
- anterior-posterior
- ASBL
- average sleep bout length
- AWBL
- average wake bout length, CT, circadian time
- DAA
- dopamine autoreceptor antagonist
- DRINK
- drinking activity
- (−)DS121
- S(−)-3-(1-propyl-3-piperidinyl)-benzonitrile hydrochloride
- EEG
- electroencephalogram
- EMG
- electromyogram
- LMA
- locomotor activity
- LMAI
- locomotor activity intensity
- ML
- medial-lateral
- MSBL
- maximum sleep bout length
- MWBL
- maximum wake bout length
- NREM
- non-rapid eye movement sleep
- REM
- rapid eye movement sleep (paradoxical sleep)
- Tb
- body temperature
- WAKE
- wakefulness
- Received October 13, 1997.
- Accepted February 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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