Modafinil [2-[(Diphenylmethyl)sulfinyl]acetamide] and Circadian Rhythms in Syrian Hamsters: Assessment of the Chronobiotic Potential of a Novel Alerting Compound

Abstract

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 ϳ50% 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.Convergent evidence indicates that the hypothalamic suprachiasmatic nucleus is the locus of the mammalian circadian clock driving daily rhythms of behavior and physiology (Klein et al

Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons

“…Saline-treated mice spent a considerable amount of time sleeping in the testing cages, resulting in a significant decline in beam breaks throughout the experiment. In accord with previous results reported by Edgar and Seidel demonstrating that modafinil increased wake time but did not increase locomotor activity above the level expected for normal waking animals (33), the results reported here show that acute exposure to modafinil can induce long-lasting wakefulness in mice, as has been shown in rats and hamsters (32,33). The acute effect of modafinil is reversible, since the locomotor activity of modafinil-treated mice returned to baseline levels the next day (data not shown).…”

“…In this study we induced prolonged wakefulness in mice either by administering modafinil or by gently handling animals during the light phase, when mice are normally asleep. Previous data from rats and Syrian hamsters showed that in vivo administration of modafinil during the light phase prolonged wakefulness and reduced slow wave and paradoxical sleep (32,33). Using modafinil could reduce the stress resulting from experimental manipulations leading to sleep loss.…”

“…Modafinil significantly enhances vigilance, alertness, and wakefulness in patients, with limited potential for addiction and without anxiogenic effects (28)(29)(30). The enhancement of wakefulness by modafinil occurs at the expense of slow-wave and paradoxical sleep, probably as a result of increasing the dopaminergic (DA) tone through the blockade of the dopamine transporter (31,32).…”

Effect of arousing stimuli on circulating corticosterone and the circadian rhythms of luteinizing hormone (LH) surges and locomotor activity in estradiol-treated ovariectomized (ovx+EB) Syrian hamsters

“…(It should be noted that herein, the term “arousal” refers to wakefulness, stimulation to action, or physiological readiness for activity (www.merriam-webster.com/dictionary/arousal). However, other methods for maintaining arousal or wakefulness, such as restraint stress, confinement to a platform over water (Mistlberger et al, 2003) or injections of caffeine (Antle et al, 2001), yohimbine or modanifil (Webb et al, 2006), do not induce phase shifts, indicating that all types of arousal do not have equivalent effects on the circadian timing system.…”

Molecular Time

“…109 Modafinil does not appear to have a chronobiotic effect, at least in the hamster. 110 Such agents have a ready market, particularly the military, the National Aeronautics and Space Administration, the trucking and airline industry, and even the health professions. However, it would still seem that increasingly the scientific and clinical evidence indicates such an approach would not be prudent in humans, for studies have indicated an increased prevalence of cancer, obesity, diabetes, and adverse cardiovascular events in shift workers, transmeridian flight crews, and patients with sleep apnea and other sleep disturbances.…”