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In Syrian hamsters, behavioral procedures for inducing arousal (e.g., running in a novel wheel or gentle handling) can shift circadian rhythms when applied during the usual sleep period ("subjective day") and can attenuate phase shifts to light during the active period ("subjective night"). This raises the possibility that drugs that affect behavioral state may have "chronobiotic" potential. We characterized the effects of modafinil (2-[(diphenylmethyl)sulfinyl]acetamide), an atypical alerting compound, on circadian rhythms in male Syrian hamsters. Electroencephalogram recordings and video observations confirmed that modafinil dose dependently increases wakefulness at the expense of slow-wave and paradoxical sleep with no increase in locomotor activity per unit of time awake. Despite inducing arousal, modafinil at these doses (150 or 300 mg/kg), administered in the subjective day or early or late in the subjective night, did not perturb circadian phase. Modafinil (300 mg/kg) also had no effect on phase shifts to light exposure either early or late in the night and did not alter the size of phase shifts induced by running in a novel wheel for 3 h during the mid-day. Modafinil (300 mg/kg) did, however, decrease by approximately 50% the amount of novel wheel-stimulated running, moving leftward the dose-response relation between wheel revolutions and shift magnitude. These results indicate that, in Syrian hamsters, modafinil alone has no significant chronobiotic efficacy. Nevertheless, this agent may increase the sensitivity of the circadian pacemaker to nonphotic stimuli and may thus have some potential as a tool for promoting clock resetting in combination with behavioral strategies.

Circadian rhythms in the Syrian hamster can be markedly phase shifted by 3 h of wheel running or arousal stimulation during their usual daily rest period ("subjective day"). Continuous wheel running is predictive but not necessary for phase shifts of this "nonphotic" type; hamsters aroused by gentle handling without running can also show maximal shifts. By contrast, physical restraint, a standard stress procedure and thus presumably arousing, is ineffective. To resolve this apparent paradox, phase-shifting effects of 3-h sessions of restraint or other stress procedures were assessed. In a preliminary study, phase shifts to arousal by gentle handling were significantly potentiated by the cortisol synthesis inhibitor metyrapone, suggesting that stress-related cortisol release may inhibit phase shifts to arousal. Next, it was confirmed that restraint in the subjective day does not induce phase shifts, but behavioral observations revealed that it also does not sustain arousal. Restraint combined with noxious compressed air blasts did sustain arousal and induced a significant cortisol response compared with arousal by gentle handling but did not induce shifts. Restraint combined with continuous horizontal rotation was also ineffective, as was EEG-validated arousal via confinement to a pedestal over water. However, 3 h of resident-intruder interactions (an intense psychosocial stress) or exposure to an open field (a mild stress) did induce large shifts that were positively correlated with indexes of forward locomotion. The results indicate that large phase shifts associated with arousal in the usual sleep period are neither induced nor prevented by stress per se, but are dependent on the expression of at least low levels of locomotor activity. Sustained arousal alone is not sufficient.