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Vol. 283, Issue 2, 757-769, 1997
Sleep Disorders Research Center, Department of Psychiatry and
Behavioral Sciences, Stanford University School of Medicine, Stanford,
California
Modafinil, a novel compound for treating excessive sleepiness, potently
increases wakefulness in laboratory rodents, cats, monkeys and humans.
Although its mechanism of action is unknown, modafinil appears to be
unlike classic stimulants. We investigated this generality by testing
the selectivity of this compound for wake-promoting effects
(e.g., relative to locomotor effects) and homeostatic
sleep responses after drug-induced waking relative to the prototypical
stimulant methamphetamine (METH). Continuous measures of
electroencephalogram (EEG) sleep-wakefulness, locomotor activity (LMA)
and body temperature (Tb) were obtained from adult male Wistar rats 3 days before and after treatment with modafinil (30, 100 and 300 mg/kg
i.p.), 0.25% methylcellulose (vehicle) or METH (0.5 and 1.0 mg/kg
i.p.). Individually housed rats in a 24-h light-dark cycle (LD 12:12)
were treated 5 h after lights-on (CT-5). LMA and Tb were monitored
via intraperitoneal telemetry. Sleep-wake stages and LMA
were recorded every 10 s, Tb every minute. During the first 3 h post-treatment, modafinil and METH significantly and dose-dependently
increased EEG wake time (P < .01 for 30 mg/kg modafinil, all
other P < .0001) and wake episode duration. Although the
cumulative increases in wakefulness were statistically equivalent, METH, but not modafinil, produced subsequent rebound hypersomnolence. At these equipotent wake-promoting doses, modafinil produced the same
total amount of REM sleep inhibition but during a longer time than
METH. Modafinil also increased LMA amount (counts/h, P < .001)
and LMA intensity (counts/min awake, P < .001) less than METH.
Both rebound hypersomnolence and increased LMA intensity, which are
undesirable features in wake-promoting drugs, were not observed after
modafinil treatment, and thus further differentiated modafinil from
amphetamine-like stimulants.
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