MODAFINIL INDUCES WAKEFULNESS WITHOUT INTENSIFYING MOTOR-ACTIVITY OR SUBSEQUENT REBOUND HYPERSOMNOLENCE IN THE RAT

Modafinil, a novel compound for treating excessive sleepiness, potentl y increases wakefulness in laboratory rodents, cats, monkeys and human s. Although its mechanism of action is unknown, modafinil appears to b e unlike classic stimulants. We investigated this generality by testin g the selectivity of this compound for wake-promoting effects (e.g., r elative to locomotor effects) and homeostatic sleep responses after dr ug-induced waking relative to the prototypical stimulant methamphetami ne (METH). Continuous measures of electroencephalogram (EEG) sleep-wak efulness, locomotor activity (LMA) and body temperature (Tb) were obta ined from adult male Wistar rats 3 days before and after treatment wit h modafinil (30, 100 and 300 mg/kg i.p.), 0.25% methylcellulose (vehic le) 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 f irst 3 h posttreatment, modafinil and METH significantly and dose-depe ndently increased EEG wake time (P < .01 for 30 mg/kg modafinil, all o ther P < .0001) and wake episode duration. Although the cumulative inc reases in wakefulness were statistically equivalent, METH, but not mod afinil, produced subsequent rebound hypersomnolence At these equipoten t wake-promoting doses, modafinil produced the same total amount of RE M sleep inhibition but during a longer time than METH. Modafinil also increased LMA amount (counts/h, P < .001) and LMA intensity (counts/mi n awake, P < .001) less than METH. Both rebound hypersomnolence and in creased LMA intensity, which are undesirable features in wake-promotin g drugs, were not observed after modafinil treatment, and thus further differentiated modafinil from amphetamine-like stimulants.