Caffeine is widely used to reduce sedation and increase alertness. However, long-term caffeine use may disrupt circadian (daily, 24-h) rhythms and thereby negatively affect health. Here, we examined the effect of caffeine on photic regulation of circadian activity rhythms in mice. We found that entrainment to a standard 12-h light, 12-h dark (LD) photocycle was delayed during oral self-administration of caffeine. Both acute, high-dose caffeine and chronic, oral caffeine exposure potentiated photic phase-delays in mice, suggesting a possible mechanism by which entrainment to LD was delayed. The effect of caffeine on photic phase-resetting was mimicked by administration of adenosine A1, but not A2A, receptor antagonist in mice. Our results support the hypothesis that caffeine interferes with the ability of the circadian clock to respond normally to light.

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults.

Background: Evidence supports a role for the circadian system in alcohol use disorders, but the impact of adolescent alcohol exposure on circadian timing later in life is unknown. Acute ethanol attenuates circadian photic phase-resetting in adult, but not adolescent, rodents. However, nearly all studies have focused on males and it is unknown whether this adolescent-typical insensitivity to ethanol persists into adulthood after adolescent drinking. Methods: Circadian activity was monitored in C57BL6/J mice receiving adolescent intermittent ethanol (AIE) exposure (15% ethanol and water every other day throughout adolescence) or water alone followed by 24 days wherein ethanol was not available (washout). Mice then received a challenge dose of ethanol (1.5 g/kg, i.p.) or saline 15 min prior to a 30-min phase-delaying light pulse, then were released into constant darkness (DD). To control for possible phase-shifting by ethanol challenge alone, a separate group of mice underwent AIE exposure (or water-only) and washout, then received an ethanol or saline injection, but did not receive a light pulse prior to DD. Results: Striking sex differences in nearly all measures of circadian photic entrainment were observed during adolescence but AIE effects were subtle and few. Only ethanol-naïve adult male mice showed attenuated photic phase-shifts with ethanol challenge, while all other groups showed normal phase-resetting responses to light. AIE-exposed females showed a persistent delay in activity offset. Conclusions: Adult male AIE-exposed mice retained adolescent-like insensitivity to ethanol-induced suppression of photic phase-resetting, suggesting AIE-induced ‘lock-in’ of an adolescent behavioral phenotype. Adult AIE-exposed females showed delayed initiation of the rest phase. Our results also indicate that intermittent ethanol drinking has subtle effects on circadian activity in mice during adolescence that differ from previously reported effects on adult males. The observed sex differences in circadian activity, ethanol consumption and preference, and responses to ethanol challenge merit future mechanistic study.

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A 55-year-old male with a past medical history significant for anxiety (on fluvoxamine 100 mg daily for the past year), obstructive sleep apnea and intermittent use of pseudoephedrine as needed for congestion (last dose was 5 days prior to admission) presented to our tertiary care emergency department with a thunderclap headache (TCH) and sudden anterograde amnesia. At 7 days prior his admission, the patient was evaluated by his dentist for a toothache that was attributed to a possible infected tooth and was subsequently treated with amoxicillin-clavulanate. Then 3 days later, he presented to an emergency department (ED) with a severe holocranial TCH and was found to be hypertensive. A non-contrast computed tomography (NCCT) of his brain did not show any acute intracranial abnormalities. A CT angiogram (CTA) of the head and neck was also unremarkable. His headache was attributed to elevated blood pressure coupled with his recent history of a toothache and he was discharged from the ED on metoprolol. Despite medical management