Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

Agostino, Patricia V.; Plano, Santiago Andrés; Golombék, Diego A.

doi:10.1073/pnas.0703388104

Cited by 67 publications

(55 citation statements)

References 51 publications

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“…After an abrupt change of the light/dark cycle, circadian rhythms gradually adapt to the new environmental conditions. Thus, resynchronization to a 6-h advance of the LD cycle usually takes 8-10 days in rodents (Agostino et al, 2007;Kiessling et al, 2010). In the present work we show that this phase shifting process transiently affected interval timing in mice.…”

Section: Discussionsupporting

confidence: 53%

Circadian modulation of interval timing in mice

et al. 2011

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Temporal perception is fundamental to environmental adaptation in humans and other animals. To deal with timing and time perception, organisms have developed multiple systems that are active over a broad range of order of magnitude, the most important being circadian timing, interval timing and millisecond timing. The circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is driven by a selfsustaining oscillator with a period close to 24 h. Time estimation in the second-to-minutes range -known as interval timing -involves the interaction of the basal ganglia and the prefrontal cortex. In this work we tested the hypothesis that interval timing in mice is sensitive to circadian modulations. Animals were trained following the peak-interval (PI) procedure. Results show significant differences in the estimation of 24-second intervals at different times of day, with a higher accuracy in the group trained at night, which were maintained under constant dark (DD) conditions. Interval timing was also studied in animals under constant light (LL) conditions, which abolish circadian rhythmicity. Mice under LL conditions were unable to acquire temporal control in the peak interval procedure.Moreover, short time estimation in animals subjected to circadian desynchronizations (modeling jet lag-like situations) was also affected. Taken together, our results indicate that short-time estimation is modulated by the circadian clock.© 2010 Elsevier B.V. All rights reserved. Keywords:Circadian rhythms Interval timingBasal ganglia Suprachiasmatic nuclei IntroductionTiming and time perception are fundamental to survival and goal reaching in humans and other animals. Organisms have developed diverse mechanisms for timing across different scales, the most important being circadian timing, interval timing and millisecond timing . The circadian pacemaker -which is driven by a self-sustaining oscillator with a period close to 24 h -is located in the suprachiasmatic nuclei (SCN) of the hypothalamus (Dunlap et al., 2004), and the principal signal that adjusts its activity is the light-dark cycle (Morin and Allen, 2006;Golombek and Rosenstein, 2010). The molecular mechanism of the endogenous circadian clock is comprised by interlocked transcription-translation feedback loops (Reppert and Weaver, 2002). On the other hand, the perception of shorter durations in the seconds-to-minutes range, known as interval timing, is crucial to learning, memory, decision making and other cognitive

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Section: Discussionsupporting

confidence: 53%

Circadian modulation of interval timing in mice

et al. 2011

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“…On a human scale, the transient cycles represent the days of gradual re-synchronization, in which physical symptoms such as tiredness and gastrointestinal upset occur (Revell and Eastman, 2005). Sildenafil, a potent and selective inhibitor of phosphodiesterase 5, has recently been shown to increase the rate of re-entrainment of hamsters following a 6 h advance of the LD cycle, decreasing the number of days required for reentrainment by up to 50% (Agostino et al, 2007). However, sildenafil did not appear to alter the number of transient cycles following a single light pulse-induced phase shift, whereas in our experiments NAN-190 sped the rate of resetting such that fewer transient cycles occurred.…”

Section: Discussionmentioning

confidence: 99%

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

2008

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Health problems can arise from de-synchrony between the external environment and the endogenous circadian rhythm, yet the circadian system is not able to quickly adjust to large, abrupt changes in the external daily cycle. In this study, we investigated the ability of to potentiate the circadian rhythm response to light as measured by phase of behavioral activity rhythms. (5 mg/kg, i.p.) was able to significantly potentiate the response to light both in dark-adapted and entrained hamsters. Furthermore, was effective even when administered up to 6 hours after light onset. Response to a light pulse was both greater in magnitude and involved fewer unstable transient cycles. Finally, was able to speed re-entrainment to a 6 h advance of the light: dark cycle by an average of 6 days when compared to vehicle-treated animals. This work suggests that compounds like NAN-190 may hold great potential as a pharmaceutical treatment for jetlag, shift work, and other circadian disorders. Keywordsserotonin; circadian; light; rhythm; jet-lag; phase shift; transient; entrainment Circadian rhythms are endogenously generated rhythms that coordinate processes such as hormone release, digestive enzyme secretion, and the sleep/wake cycle. In mammals, the major pacemaker is located in the suprachiasmatic nucleus (SCN) in the brain, which uses environmental cues to synchronize, or entrain, internal rhythms to the external surroundings (Rusak and Zucker, 1979; Ralph et al., 1990). Jetlag occurs when internal circadian rhythms become desynchronized from the external time. In humans, this desynchronization results in acute negative effects such as lowered performance levels on the job, difficulty sleeping at the appropriate times, and gastrointestinal problems. If frequent or prolonged, circadian desynchrony may be associated with more chronic health problems in people such as increased risk of breast cancer, cardiovascular disease, reproductive difficulties and peptic ulcers (Knutsson, 2003;Megdal et al., 2005). Studies using laboratory animals even link jetlag with increased rate of tumor growth and increased mortality in aged mice (Davidson et al., 2006;Filipski et al., 2004). Given the detrimental effects, studies have investigated several different methods to reduce circadian desynchrony. Melatonin, exposure to bright light, and gradual shifting of the sleep/wake cycle prior to jet travel in varying combinations have all been shown *Corresponding author. Tel: 1-413-585-3925; fax: 1-413-585-3786. E-mail address: mharring@email.smith.edu (M. Harrington). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the ...

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“…Most treatments are based on preflight plans, including long-term light conditioning, sometimes in combination with timed melatonin administration (6). It has recently been shown that in hamsters, the phosphodiesterase inhibitor sildenafil enhances circadian responses to light and accelerates reentrainment after phase advances of the LD cycle (53).…”

Section: Clock Gene Desynchronization During Jet Lag Differentially Amentioning

confidence: 99%

Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag

2010

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Jet lag encompasses a range of psycho-and physiopathological symptoms that arise from temporal misalignment of the endogenous circadian clock with external time. Repeated jet lag exposure, encountered by business travelers and airline personnel as well as shift workers, has been correlated with immune deficiency, mood disorders, elevated cancer risk, and anatomical anomalies of the forebrain. Here, we have characterized the molecular response of the mouse circadian system in an established experimental paradigm for jet lag whereby mice entrained to a 12-hour light/12-hour dark cycle undergo light phase advancement by 6 hours. Unexpectedly, strong heterogeneity of entrainment kinetics was found not only between different organs, but also within the molecular clockwork of each tissue. Manipulation of the adrenal circadian clock, in particular phase-shifting of adrenal glucocorticoid rhythms, regulated the speed of behavioral reentrainment. Blocking adrenal corticosterone either prolonged or shortened jet lag, depending on the time of administration. This key role of adrenal glucocorticoid phasing for resetting of the circadian system provides what we believe to be a novel mechanism-based approach for possible therapies for jet lag and jet lag-associated diseases.

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Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

Cited by 67 publications

References 51 publications

Circadian modulation of interval timing in mice

Circadian modulation of interval timing in mice

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag

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