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

Abstract

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 ...

Photic and nonphotic responses of the circadian clock in serotonin-deficient Pet-1 knockout mice

“…This could indicate that our results may be due, at least partially, to changes in 5-HT 1B receptor density or sensitivity caused by deletion of the Pet-1 gene. Despite the fact that there are several studies showing that 5-HT antagonists are able to potentiate phase advances in hamsters (Gannon, 2003;Kessler et al, 2008;Lall & Harrington, 2006), our results showing no differences in the phase-advance portion of the PRC between WT and Pet-1 KO animals are similar to experiments in 5,7-DHT-treated hamsters that showed no effect of 5-HT depletion on phase advances in response to light pulses (Morin & Blanchard, 1991).…”

“…Administration of 8-OH-DPAT attenuates both phase delays and advances of wheel-running behavior in response to a light pulses . Conversely, administration of a 5-HT receptor antagonist has been shown to potentiate light-induced phase delays (Rea et al, 1995;Smart & Biello, 2001) and advances (Gannon, 2003;Kessler et al, 2008;Lall & Harrington, 2006). Additionally, mice that received neurotoxic lesions of the 5-HT system have been shown to exhibit larger magnitude phase delays and corresponding increases in Fos induction in response to light pulses given during the early subjective night (Bradbury et al, 1997).…”

“…Similarly, in hamsters, administration of (AE)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT 1A/7 receptor agonist, attenuates both light-induced phase advances and delays of wheel-running behavior , and pretreatment with 5-HT agonists (including 8-OH-DPAT) attenuates Fos induction in response to a light pulse given during the early subjective night Rea et al, 1994;Selim et al, 1993). Conversely, administration of a 5-HT 1A receptor antagonist has been shown to potentiate light-induced phase delays (Rea et al, 1995;Smart & Biello, 2001) and advances (Gannon, 2003;Kessler et al, 2008;Lall & Harrington, 2006). In mice, depletion of 5-HT by application of 5,7dihydroxytryptamine (5,7-DHT) to the SCN causes larger phase delays and increased Fos induction in response to a light pulse given during the mid-subjective night (Bradbury et al, 1997).…”

Location, location, location: important for jet-lagged circadian loops

“…This adds to several recent observations that pharmacological treatments can speed adjustment to shifted light/dark cycles; for example, jet lag has been shown to be lessened in hamsters treated with sildenafil (19) or NAN-190, a drug that alters serotonin responses (20). Further development of such compounds might reduce the negative health consequences of jet lag and shift work.…”

Effects of Circadian Disruption on Physiology and Pathology: From Bench to Clinic (and Back)

“…This can be done either indirectly, for instance by enhancing serotonergic transmission from the raphe nuclei to the SCN (Lall et al 2012), which accelerates the re-entrainment to a 6 h LD-advance (Kessler et al 2008) or directly by pharmacological targeting of photic second messengers, as increasing the cGMP-GC-PKG signal transduction by inhibiting cGMP enzymatic degradation, which accelerates re-entrainment after an abrupt 6 h LD-advance (Agostino et al 2007;Plano et al 2012).…”