Methylphenidate is one of the most common pharmaceutical treatments for Attention Deficit Hyperactive Disorder (ADHD). It is also gaining popularity as a cognitive enhancement and recreational substance. The current study assesses the long-term effects of methylphenidate (MPD) on the circadian rhythm activity pattern of adolescent and adult male Sprague-Dawley (SD) rats. The experiment lasted for 11 days of non-stop recording, the evaluation was divided into 4 phases: acute, induction, washout, and expression phases. Circadian rhythm changes in each phase were compared between the adolescent and adult rats using the following parameters MESOR (midline estimating statistic of rhythm) or average activity, amplitude (distance from MESOR to the peak activity), and acrophase (time at which peak amplitude occurs). Overall, more significant changes in circadian rhythm pattern among adult rats were observed as compared to adolescent rats. As the circadian rhythm governs the diurnal locomotor activity pattern, changes in the locomotor pattern induced by chronic treatment MPD indicate that the drug exerts a long-term effect on the circadian rhythm.
KeywordsCircadian RhythmAdolescentAdult
Godfrey, J. (2009) Safety of Therapeutic Methyphenidate in Adults: A Systematic Review of the Evidence. Journal of Psychopharmacology, 23, 194-205. http://dx.doi.org/10.1177/0269881108089809
Askenasy, E.O., Taber, K.H., Yang, P.B. and Dafny, N. (2007) Methylphenidate (Ritalin): Behavioral Studies in the Rat. International Journal of Neuroscience, 117, 1-38. http://dx.doi.org/10.1080/00207450600910176
Patrics, K.S. and Markowitz, J.C. (1997) Pharmacology of Methylphenidate, Amphetamine, Enantiomers and Penoline in Attention Deficit/Hyperactivity Disorder. Human Pharmacology, 12, 527-546.
Volkow, N.D., Fowler, J.S., Hitzemann, P. and Wang, G.I. (1996) Neurochemical Mechanism Underlying Responses to Psychostimulants. NIDA Research Monograph, 159, 322-348.
Accardo, P. and Blondis, T.A. (2001) What’s All the Fuss about Ritalin? The Journal of Pediatrics, 138, 6-9. http://dx.doi.org/10.1067/mpd.2001.111505
Gerasimov, M.D., Franceschi, M., Volkow, N.D., Gifford, A., Gatley, S.J., Marsteller, D., Molina, P.E. and Dewey, S.L. (2000) Comparison between Intraperitoneal and Oral Methylphenidate Administration: A Microdialysis and Locomotor Activity Study. Journal of Pharmacology and Experimental Therapeutics, 296, 51-57.
Levin, F.R. and Kleber, H.D. (1995) Attention-Deficit Hyperactivity Disorder and Substance Abuse: Relationships and Implications for Treatment. Harvard Review of Psychiatry, 2, 246-258. http://dx.doi.org/10.3109/10673229509017144
Greely, H., Sahakian, B., Harris, J., Kessler, R.C., Gazzaniga, M., Campbell, P. and Farah, M.J. (2008) Towards Responsible Use of Cognitive-Enhancing Drugs by the Healthy. Nature, 456, 702-705. http://dx.doi.org/10.1038/456702a
Stix, G. (2009) Turbocharging the Brain. Scientific American, 301, 46-50. http://dx.doi.org/10.1038/scientificamerican1009-46
Bergheimm, M., Yang, P.B., Burau, K.D. and Dafny, N. (2012) Adolescent Rat Circadian Activity Is Modulated by Psychostimulants. Brain Research, 1431, 35-45. http://dx.doi.org/10.1016/j.brainres.2011.10.027
Glasser, A.U., Reyes-Vasquez, C., Burau, K.D. and Dafny, N. (2012) Continue Morphine Administration and Abrupt Cessation Alters the Normal Loco-motor Circadian Activity Pattern. Pharmacology Biochemistry and Behavior, 101, 544-552. http://dx.doi.org/10.1016/j.pbb.2012.02.015
Jones, Z. and Dafny, N. (2013) Acute and Chronic Dose Response Effect of Methylphenidate on Ventral Tegmental Area Neurons Correlated with Animal Behavior. Brain Research Bulletin, 96, 86-92.
Klein, D.C., Moore, R.Y. and Reppert, S.M. (1991) Suprachiasmatic Nucleus: The Mind’s Clock. Oxford University Press, New York.
Antle, M.C., Van Diepen, H.C., Deboer, T., Pedram, P., Rodrigues Pereira, R. and Meijer, J.H. (2012) Methylphenidate Modifies the Motion of the Circadian Clock. Neuropsy-chopharmacology, 37, 2446-2455. http://dx.doi.org/10.1038/npp.2012.103
Gaytan, O., Yang, P., Swann, A. and Dafny, N. (2000) Diurnal Differences in Sensitization to Methylphenidate. Brain Research, 864, 24-39. http://dx.doi.org/10.1016/S0006-8993(00)02117-X
Lee, M.J., Yang, P.B., Wilcox, V.I., Burau, K.P., Swann, A.C. and Dafny, N. (2011) Repetitive Methylphenidate Administration Modultaes the Diurnal Behavioral Activity Pattern of Adult Female SD Rats. Journal of Neural Transmission, 118, 285-298.
Trinh, N.T., Kohlleppel, S., Wilcox, V.T., Burau, K. and Dafny, N. (2013) Adult Female Rats Altered Diurnal Locomotor Activity Pattern Following Chronic Methylphenidate Treatment. Journal of Neural Transmission, 120, 1717-1731.
Giorgetti, M. and Zhdanova, I.V. (2000) Chronic Cocaine Treatment Induces Dysregulation in the Circadian Pattern of Rats’ Feeding Behavior. Brain Research, 877, 170-175. http://dx.doi.org/10.1016/S0006-8993(00)02671-8
Gray, J.D., Punsoni, M., Tabori, N.E., Melton, J.T., Fanslow, V., Ward, M.J., et al. (2007) Methylphenidate Administration in Juvenile Rats Alters Brain Areas Involved in Initiation, Motivated Behaviors, Appetite, and Stress. The Journal of Neuroscience, 27, 7196-7207. http://dx.doi.org/10.1523/JNEUROSCI.0109-07.2007
Gaytan, O., Al-Rahim, S., Swann, A. and Dafny, N. (1997) Sensitization to Locomotor Effects of Methylphenidate in the Rat. Life Sciences, 61, PL101-PL107.
Gaytan, O., Al-Rahim, S. and Swann, A. (1998) Diurnal Differences in Rats Motor Response to Amphetamine. European Journal of Pharmacology, 345, 119-128. http://dx.doi.org/10.1016/S0014-2999(97)01558-6
Lee, M.J., Burau, K.D. and Dafny, N. (2013) Behavioral Daily Rhythmic Activity Pattern of Adolescent Female Rats Is Modulated by Acute and Chronic Cocaine. Journal of Neural Transmission, 120, 733-744.
Dafny, N. and Yang, P.B. (2006) The Role of Age, Genotype, Sex, and Route of Acute and Chronic Administration of Methylphenidate: A Review of Its Locomotor Effects. Brain Research Bulletin, 68, 393-405. http://dx.doi.org/10.1016/j.brainresbull.2005.10.005
Kalivas, P.W., Pierce, R.C., Cornish, J. and Sorg, B.A. (1998) A Role for Sensitization in Craving and Relapse in Cocaine Addiction. Journal of Psychopharmacology, 122, 49-53. http://dx.doi.org/10.1177/026988119801200107
Yang, P.B., Behrang, A., Swann, A.C. and Dafny, N. (2003) Strain Differences in the Behavioral Responses of Male Rats to Chronically Administered Methylphenidate. Brain Research, 971, 139-152. http://dx.doi.org/10.1016/S0006-8993(02)04240-3
Yang, P.B., Swann, A.C. and Dafny, N. (2006) Acute and Chronic Methylphenidate Dose-Response Assessment on Three Adolescent Male Rat Strains. Brain Research Bulletin, 71, 301-310. http://dx.doi.org/10.1016/j.brainresbull.2006.09.019
Yang, P.B., Atkins, K.D. and Dafny, N. (2011) Behavioral Sensitization and Cross-Sensitization between Methylphenidate Amphetamine, and 3,4-Methylenedioxymethamphetamine (MDMA) in Female SD Rats. European Journal of Pharmacology, 66, 72-85. http://dx.doi.org/10.1016/j.ejphar.2011.04.035
Hovens, J.G., Cantwell, D.P. and Kiriakos, R. (1994) Psychiatric Comorbidity in Hospitalized Adolescent Substance Abusers. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 476-483. http://dx.doi.org/10.1097/00004583-199405000-00005
Massello, W.I. and Carpenter, D.A. (1999) A Fatality Due to the Intranasal Abuse of Methylphenidate (Ritalin). Journal of Forensic Sciences, 44, 220-221.
Parran Jr., T.V. and Jasinski, D.R. (1991) Intravenous Methylphenidate Abuse: Prototype for Prescription Drug Abuse. Archives of Internal Medicine, 151, 781-783. http://dx.doi.org/10.1001/archinte.1991.00400040119027
Huttenlocher, P.R. (1979) Synaptic Density in Human Frontal Cortex-Developmental Changes and Effects of Aging. Brain Research, 163, 195-205. http://dx.doi.org/10.1016/0006-8993(79)90349-4
Rakie, P. (1986) Development of the Primate Cerebral Cortex. In: Lewis, M., Ed., Child and Adolescent Psychiatry, Williams and Wilkins, Baltimore.
Amini, B., Yang, P.B., Swann, A.C. and Dafny, N. (2004) Differential Locomotor Responses in Male Rats from Three Strai to Acute Methylphenidate. International Journal of Neuroscience, 114, 1063-1084. http://dx.doi.org/10.1080/00207450490475526
Alghim, M.F., Yang, P.B., Wilcox, V.T., Burau, K.D., Swann, A.C. and Dafny, N. (2009) Prolonged Methylphenidate Treatment Alters the Behavioral Diurnal Activity Pattern of Adult Male Sprague-Dawley Rats. Pharmacology Biochemistry and Behavior, 92, 93-99.
Reppert, S.M. and Weaver, D.R. (2002) Coordination of Circadian Timing in Mammals. Nature, 418, 935-941. http://dx.doi.org/10.1038/nature00965
Kollins, S.M., MacDonald, E.K. and Rush, C.R. (2001) Assessing the Abuse Potential of Methylphenidate in Nonhuman and Human Species: A Review. Pharmacology Biochemistry and Behavior, 68, 611-627.
Lee, M.J., Yang, P.B., Wilcox, V.T., Burau, K.D., Swann, A.C. and Dafny, N. (2009) Does Repetitive Ritalin Injection Produce Long-Term Effect on SD Female Adolescent Rats? Neuropharmacology, 57, 201-207.
Vitaona, M.H., Takahashi, J.S. and Turek, F.W. (2001) Overview of Circadian Rhythms. Alcohol Research Health, 25, 85-93.
Nestler, E.J. (2004) Molecular Mechanism of Drug Addiction. Neuropharmacology, 47, 24-32. http://dx.doi.org/10.1016/j.neuropharm.2004.06.031
Kim, Y., Taylor, M.A., Baron, M., Sands, A., Nairn, A.C. and Greengard, P. (2009) Methylphenidate Induced Dendritic Spine Formation and ΔFosB Expression in Nucleus Accumbens. Proceedings of the National Academy of Sciences of the United States of America, 106, 2915-2920. http://dx.doi.org/10.1073/pnas.0813179106
Robinson, T.E. and Kolb, B. (1999) Alteration in the Morphology of Dendrites and Dendritic Spines in the Nucleus Accumbens and Prefrontal Cortex Following Repeated Treatment with Amphetamine and Cocaine. European Journal of Neuroscience, 11, 1598-1604. http://dx.doi.org/10.1046/j.1460-9568.1999.00576.x
Robinson, T.E. and Kolb, B. (2004) Structural Plasticity Associated with Exposure to Drug of Abuse. Neuropharmacology, 47, 33-46.
Adriani, W., Chiarotti, F. and Laviola, G. (1998) Elevated Novelty Seeking and Peculiar d-Amphetamine Sensitization in Periadolescent Mice Compared with Adult Mice. Behavioral Neuroscience, 112, 1152-1156. http://dx.doi.org/10.1037/0735-7044.112.5.1152
Bowman, B.P. and Kuhn, C.M. (1996) Age-Related Differences in the Chronic and Acute Response to Cocaine in the Rat. Developmental Psychobiology, 29, 597-611. http://dx.doi.org/10.1002/(SICI)1098-2302(199611)29:7 3.0.CO;2-P
Laviola, G., Wood, R.D., Kuhn, C., Francis, R. and Spear, L.P. (1995) Cocaine Sensitization in Periadolescent and Adult Rats. The Journal of Pharmacology and Experimental Therapeutics, 275, 345-357.
Roffman, J.L. and Raskin, L.A. (1997) Stereotyped Behavior: Effects of d-Amphetamine and Methylphenidate in the Young Rat. Pharmacology Biochemistry and Behavior, 58, 1095-1102. http://dx.doi.org/10.1016/S0091-3057(97)00321-3
Andersen, S.L., Arvaniitaglannis, S.A., Pliakas, A.M., LeBlance, C. and Carleron, W.A. (2002) Altered Responsiveness to Cocaine in Rats Exposed to Methylphenidate during Development. Nature Neuroscience, 51, 13-14. http://dx.doi.org/10.1038/nn777
Andersen, S.L. and Teicher, M.H. (2000) Sex Differences in Dopamine Receptors and Their Relevance to ADHD. Neuroscience Biobehavioral Reviews, 24, 137-141. http://dx.doi.org/10.1016/S0149-7634(99)00044-5
Insel, T.R. and Charney, D.S. (2003) Research on Major Depression Strategies and Priorities. Journal of the American Medical Association, 289, 3167-3168. http://dx.doi.org/10.1001/jama.289.23.3167
Bolanos, C.A., Glatt, S.J. and Jackson, D. (1998) Subsensitivity to Dopaminergic Drugs in Periadolescent Rats: A Behavioral and Neurochemical Analysis. Developmental Brain Research, 111, 25-33. http://dx.doi.org/10.1016/S0165-3806(98)00116-3
Dell’Anna, M.E., Luthman, J., Landqvist, E. and Olson, L. (1993) Development of Monoamine Systems after Neonatal Anoxia in Rats. Brain Research Bulletin, 32, 159-170. http://dx.doi.org/10.1016/0361-9230(93)90070-R
Spear, L.P. and Brake, S.C. (1983) Periadolescence: Age-Dependent Behavior and Psychopharmacological Responsivity in Rats. Developmental Psychobiology, 16, 83-109. http://dx.doi.org/10.1002/dev.420160203
White, P.J. and Kalivas, P.W. (1998) Neuroadaptations Involved in Amphetamine and Cocaine Addiction. Drug and Alcohol Dependence, 51, 141-153. http://dx.doi.org/10.1016/S0376-8716(98)00072-6
McDougall, S.A., Collins, R.L., Karper, P.E., Watson, J.B. and Crawford, C.A. (1999) Effects of Repeated Methylphenidate Treatment in the Young Rat: Sensitization to Both Locomotor Activity and Stereotyped Sniffing. Experimental and Clinical Psychopharmacology, 7, 208-218. http://dx.doi.org/10.1037/1064-1297.7.3.208
Brandon, C.L., Marinelli, M., Baker, L.K. and White, F.J. (2001) Enhanced Reactivity and Vulnerability to Cocaine Following Methylphenidate Treatment in Adolescent Rats. Neuropsychopharmacology, 25, 651-661. http://dx.doi.org/10.1016/S0893-133X(01)00281-0
Andreazza, A.C., Frey, B.N. and Valvassori, S.S. (2007) DNA Damage in Rats after Treatment with Methylphenidate. Progress in Neuro-Psychopharmacology, Biological Psychiatry, 31, 1282-1288.
Dougherty, D.D., Bonab, A.A., Spencer, T.J., Ranch, S.L., Madras, B.K. and Fischman, A.J. (1996) Dopamine Transporter Density in Patients with Attention Deficit Hyperactivity Disorder. The Lancet, 9196, 2132-2133.