Methylphenidate Modifies the Motion of the Circadian Clock
Open accessAbstract
People with attention-deficit/hyperactivity disorder (ADHD) often experience sleep problems, and these are frequently exacerbated by the methylphenidate they take to manage their ADHD symptoms. Many of the changes to sleep are consistent with a change in the underlying circadian clock. The present study was designed to determine if methylphenidate alone could alter properties of the circadian clock. Young male mice were examined in light-dark cycles and in constant darkness and recordings were performed on behavioral activity, sleep, and electrical activity in the suprachiasmatic nucleus (SCN) of freely moving mice. Methylphenidate in the drinking water (0.08%) significantly increased activity in the mid-to-late night, and led to a delay in the onset of activity and sleep relative to the light-dark cycle. While locomotor levels returned to baseline after treatment ended, the phase angle of entrainment required at least a week to return to baseline levels. In constant darkness, the free-running period of both wheel-running and general locomotor rhythms was lengthened by methylphenidate. When the treatment ended, the free-running period either remained stable or only partially reverted to baseline levels. Methylphenidate also altered the electrical firing rate rhythms in the SCN. It induced a delay in the trough of the rhythm, an increment in rhythm amplitude, and a reduction in rhythm variability. These observations suggest that methylphenidate alters the underlying circadian clock. The observed changes are consistent with clock alterations that would promote sleep-onset insomnia.
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MPH increases the activity at mid-to-late night and leads to a delay in sleep relative to the light-dark cycle.
“MPH increases the activity at mid-to-late night and leads to a delay in sleep relative to the light–dark cycle [209]; but the mechanisms of MPH involved in the circadian rhythm are unknown.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [209]
Animal studies indicate that stimulant and non-stimulant medications can impact circadian processes.
“Animal studies indicate that stimulant and non-stimulant medications can impact on circadian processes (e.g. Antle et al. 2012; Baird et al. 2013; O'Keeffe et al. 2012).”
From A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder (2017) · cites this paper as Antle et al. 2012
Cites
Principles and Practice of Sleep Medicine
Kryger, M. H., Roth, T. G., & Dement, W. C. (2011) · Elsevier eBooks · doi:10.1016/c2009-0-59875-3 · Cited by 5,118 · see citing works
Effects of Sleep Deprivation on Performance: A Meta-Analysis
Pilcher, J. J., & Huffcutt, A. I. (1996) · Sleep · doi:10.1093/sleep/19.4.318 · Cited by 1,549 · see citing works
Sleep Homeostasis and Models of Sleep Regulation
Borb, A. A., & Achermann, P. (1999) · Journal of Biological Rhythms · doi:10.1177/074873099129000894 · Cited by 1,503 · see citing works
Eilers, P. H. C. (2003) · Analytical Chemistry · doi:10.1021/ac034173t · Cited by 1,347 · see citing works
Orchestrating time: arrangements of the brain circadian clock
Antle, M. C., & Silver, R. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.01.003 · Cited by 463 · see citing works
Self-citationHuber, R., Deboer, T., & Tobler, I. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02248-9 · Cited by 313 · see citing works
Self-citationVan Veen, M. M., Kooij, J. J. S., Boonstra, A. M., Gordijn, M. C. M., & Van Someren, E. J. W. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.032 · Cited by 300 · see citing works
Sleep Neurobiology from a Clinical Perspective
España, R. A., & Scammell, T. E. (2011) · SLEEP · doi:10.5665/sleep.1112 · Cited by 282 · see citing works
Koda, K., Ago, Y., Cong, Y., Kita, Y., Takuma, K., & Matsuda, T. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06750.x · Cited by 222 · see citing works
Consequences of Sleep Loss or Sleep Disruption in Children
Sadeh, A. (2007) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2007.05.012 · Cited by 220 · see citing works
Regularly scheduled voluntary exercise synchronizes the mouse circadian clock
Edgar, D. M., & Dement, W. C. (1991) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1991.261.4.r928 · Cited by 219 · see citing works
Effects of Atomoxetine and Methylphenidate on Sleep in Children With ADHD
Sangal, R. B., Owens, J., Allen, A. J., Sutton, V., Schuh, K., & Kelsey, D. (2006) · Sleep · doi:10.1093/sleep/29.12.1573 · Cited by 214 · see citing works
Edgar, D. M., Martin, C. E., & Dement, W. C. (1991) · Journal of Biological Rhythms · doi:10.1177/074873049100600301 · Cited by 187 · see citing works
Rhythmic Properties of the Hamster Suprachiasmatic Nucleus In Vivo
Yamazaki, S., Kerbeshian, M. C., Hocker, C. G., Block, G. D., & Menaker, M. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-24-10709.1998 · Cited by 184 · see citing works
Boonstra, A. M., Kooij, J. J. S., Oosterlaan, J., Sergeant, J. A., Buitelaar, J. K., & Van Someren, E. J. W. (2007) · Sleep · doi:10.1093/sleep/30.4.433 · Cited by 155 · see citing works
Sobanski, E., Schredl, M., Kettler, N., & Alm, B. (2008) · Sleep · doi:10.1093/sleep/31.3.375 · Cited by 153 · see citing works
Free-access to a running wheel shortens the period of free-running rhythm in blinded rats
Yamada, N., Shimoda, K., Ohi, K., et al. (1988) · Physiology & Behavior · doi:10.1016/0031-9384(88)90265-x · Cited by 145 · see citing works
Entrainment and phase shifting of circadian rhythms in mice by forced treadmill running
Marchant, E. G., & Mistlberger, R. E. (1996) · Physiology & Behavior · doi:10.1016/s0031-9384(96)80045-x · Cited by 145 · see citing works
Long Term Effects of Sleep Deprivation on The Mammalian Circadian Pacemaker
Deboer, T., Détári, L., & Meijer, J. H. (2007) · SLEEP · doi:10.1093/sleep/30.3.257 · Cited by 142 · see citing works
Self-citationSleep Homeostasis and Models of Sleep Regulation
Achermann, P., & Borbély, A. A. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4160-6645-3.00037-2 · Cited by 140 · see citing works
Subjective and objective measures of sleep in children with attention-deficit/hyperactivity disorder
Owens, J., Sangal, R. B., Sutton, V. K., Bakken, R., Allen, A. J., & Kelsey, D. K. (2008) · Sleep Medicine · doi:10.1016/j.sleep.2008.03.013 · Cited by 138 · see citing works
Kissling, C., Retz, W., Wiemann, S., Coogan, A. N., Clement, R. M., Hünnerkopf, R., Conner, A. C., Freitag, C. M., Rösler, M., & Thome, J. (2008) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30602 · Cited by 109 · see citing works
Amplitude of the SCN Clock Enhanced by the Behavioral Activity Rhythm
van Oosterhout, F., Lucassen, E. A., Houben, T., vanderLeest, H. T., Antle, M. C., & Meijer, J. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039693 · Cited by 105 · see citing works
Self-citationCorkum, P. V., Panton, R., Ironside, S., Macpherson, M. J., & Williams, T. (2007) · Journal of Pediatric Psychology · doi:10.1093/jpepsy/jsm106 · Cited by 98 · see citing works
Disorganization of the rat activity rhythm by chronic treatment with methamphetamine
Honma, K., Honma, S., & Hiroshige, T. (1986) · Physiology & Behavior · doi:10.1016/0031-9384(86)90265-9 · Cited by 93 · see citing works
Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent
Mistlberger, R. E., & Antle, M. C. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01269-9 · Cited by 86 · see citing works
Self-citationGALLAND, B. C., TRIPP, E. G., & TAYLOR, B. J. (2009) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2009.00795.x · Cited by 85 · see citing works
IRONSIDE, S., DAVIDSON, F., & CORKUM, P. (2010) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2010.00845.x · Cited by 84 · see citing works
Response of the Mouse Circadian System to Serotonin 1A/2/7 Agonists in vivo: Surprisingly Little
Antle, M. C., Ogilvie, M. D., Pickard, G. E., & Mistlberger, R. E. (2003) · Journal of Biological Rhythms · doi:10.1177/0748730403251805 · Cited by 82 · see citing works
Self-citationBobrzynska, K. J., & Mrosovsky, N. (1998) · Journal of Comparative Physiology A · doi:10.1007/s003590050175 · Cited by 81 · see citing works
Opposing effects of behavioural activity and light on neurons of the suprachiasmatic nucleus
Schaap, J., & Meijer, J. H. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01561.x · Cited by 75 · see citing works
Self-citationSleep-related Disorders in ADHD: A Review
van der Heijden, K. B., Smits, M. G., & Gunning, W. B. (2005) · Clinical Pediatrics · doi:10.1177/000992280504400303 · Cited by 75 · see citing works
Actigraphic Monitoring During Sleep of Children With ADHD on Methylphenidate and Placebo
SCHWARTZ, G., AMOR, L. B., GRIZENKO, N., LAGEIX, P., BARON, C., BOIVIN, D. B., & JOOBER, R. (2004) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000135802.94090.93 · Cited by 70 · see citing works
Nováková, M., Paclt, I., Ptáček, R., Kuželová, H., Hájek, I., & Sumová, A. (2011) · Chronobiology International · doi:10.3109/07420528.2011.596983 · Cited by 66 · see citing works
Houben, T., Deboer, T., van Oosterhout, F., et al. (2009) · Journal of Biological Rhythms · doi:10.1177/0748730409349895 · Cited by 65 · see citing works
Self-citationSerotonergic Modulation of Photic Entrainment in the Syrian Hamster
Rea, M. A., & Pickard, G. E. (2000) · Biological Rhythm Research · doi:10.1076/0929-1016(200007)31:3;1-k;ft284 · Cited by 58 · see citing works
Relationship between free-running period and motor activity in blinded rats
Yamada, N., Shimoda, K., Takahashi, K., & Takahashi, S. (1990) · Brain Research Bulletin · doi:10.1016/0361-9230(90)90261-w · Cited by 57 · see citing works
Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat
Gaytan, O., Ghelani, D., Martin, S., Swann, A. C., & Dafny, N. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00880-9 · Cited by 55 · see citing works
Algahim, M. F., Yang, P. B., Wilcox, V. T., Burau, K. D., Swann, A. C., & Dafny, N. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.10.021 · Cited by 52 · see citing works
Mrosovsky, N. (1999) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00022-0 · Cited by 51 · see citing works
Zhou, M., Rebholz, H., Brocia, C., Warner‐Schmidt, J. L., Fienberg, A. A., Nairn, A. C., Greengard, P., & Flajolet, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915173107 · Cited by 51 · see citing works
Short light–dark cycles affect sleep in mice
Deboer, T., Ruijgrok, G., & Meijer, J. H. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05964.x · Cited by 46 · see citing works
Self-citationRunning wheel size influences circadian rhythm period and its phase shift in mice
Deboer, T., & Tobler, I. (2000) · Journal of Comparative Physiology A · doi:10.1007/s003590000150 · Cited by 44 · see citing works
Self-citationThe noradrenaline reuptake inhibitor atomoxetine phase-shifts the circadian clock in mice
O'Keeffe, S., Thome, J., & Coogan, A. N. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.11.002 · Cited by 43 · see citing works
Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats?
Lee, M. J., Yang, P. B., Wilcox, V. T., Burau, K. D., Swann, A. C., & Dafny, N. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.06.008 · Cited by 42 · see citing works
Sinclair, S. V., & Mistlberger, R. E. (1997) · Behavioural Brain Research · doi:10.1016/s0166-4328(96)02274-7 · Cited by 33 · see citing works
Manjanatha, M. G., Shelton, S. D., Dobrovolsky, V. N., Shaddock, J. G., McGarrity, L. G., Doerge, D. R., Twaddle, N. W., Lin, C., Chen, J. J., Mattison, D. R., et al. (2008) · Environmental and Molecular Mutagenesis · doi:10.1002/em.20407 · Cited by 27 · see citing works
Locomotor rhythms induced by methylphenidate in suprachiasmatic nuclei-lesioned rats
Honma, S., & Honma, K. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90289-j · Cited by 15 · see citing works
Lee, M. J., Yang, P. B., Wilcox, V. T., Burau, K. D., Swann, A. C., & Dafny, N. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0510-8 · Cited by 13 · see citing works
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Coogan, A. N., & McGowan, N. M. (2017) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-016-0214-5 · Cited by 208 · see citing works
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Korshunov, K. S., Blakemore, L. J., & Trombley, P. Q. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00091 · Cited by 173 · see citing works
Quintero, J., Gutiérrez-Casares, J. R., & Álamo, C. (2022) · Neurology and Therapy · doi:10.1007/s40120-022-00392-2 · Cited by 70 · see citing works
“MPH increases the activity at mid-to-late night and leads to a delay in sleep relative to the light–dark cycle [209]; but the mechanisms of MPH involved in the circadian rhythm are unknown.”
BackgroundThe use of actigraphy in the monitoring of methylphenidate versus placebo in ADHD: a meta-analysis
De Crescenzo, F., Armando, M., Mazzone, L., Ciliberto, M., Sciannamea, M., Figueroa, C., Janiri, L., Quested, D., & Vicari, S. (2014) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-013-0122-x · Cited by 48 · see citing works
Baird, A. L., Coogan, A. N., Kaufling, J., Barrot, M., & Thome, J. (2013) · Brain Research · doi:10.1016/j.brainres.2013.03.038 · Cited by 46 · see citing works
- Authors
- Antle, M. C., van Diepen, H. C., Deboer, T., Pedram, P., Pereira, R. R., & Meijer, J. H.
- Affiliations
- University of Calgary (CA)
- Leiden University Medical Center (NL)
- Maasstad Ziekenhuis (NL)
- Corresponding author
- Antle, Michael C
- Venue
- Neuropsychopharmacology
- Published
- 2012-07-04
- Volume
- 37
- Issue
- 11
- Pages
- 2446-2455
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3445990
- OpenAlex
- W1973978893
- Cited by
- 52
- References
- 49
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 8 · 2013: 7
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (818.02.016)
- Natural Sciences and Engineering Research Council of Canada
- Stichting voor de Technische Wetenschappen
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- methylphenidate, circadian clock, attention deficit hyperactivity disorder, sleep disorders, suprachiasmatic nucleus, free-running period, circadian entrainment, sleep onset insomnia, locomotor activity rhythm, constant darkness, clock gene expression
- MeSH terms
- Action Potentials, Central Nervous System Stimulants, Animals, Behavior, Animal, Circadian Rhythm, Dark Adaptation, Electric Stimulation, Electrodes, Implanted, Male, Methylphenidate, Mice, Inbred C57BL, Motor Activity, Suprachiasmatic Nucleus, Wakefulness, Mice, Circadian Clocks
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