Protective effects of forced exercise against methylphenidate-induced anxiety, depression and cognition impairment in rat


1 Department of Pharmacology, School of Medicine and Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran

2 Department of Physiology, Faculty of Veterinary Medicine, Tehran University, Tehran, Iran


Background: Methylphenidate (MPH), a neural stimulant, can cause damages to brain; the chronic neurochemical and behavioral effects of MPH remain unclear. Exercise lowers stress and anxiety and can act as non-pharmacologic neuroprotective agent. In this study protective effects of exercise in MPH-induced anxiety, depression and cognition impairment were investigated.
Materials and Methods: Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control, received normal saline (0.2 ml/rat) for 21 days, group 2 and 3 (as positive controls) received MPH (10 and 20 mg/kg) for 21 days. Groups 4 and 5 concurrently were treated with MPH (10 and 20 mg/kg) and forced exercise for 21 days. On day 21, Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST) and Tail Suspension Test (TST) were used to investigate the level of anxiety and depression in animals. In addition between 17 th and 21 th days, Morris Water Maze (MWM) was applied to evaluate the effect of MPH on spatial learning and memory.
Results: MPH-treated animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM and TST which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. Forced exercise by treadmill can attenuate MPH-induced anxiety, depression and motor activity alteration in OFT. MPH also can disturb learning and memory in MWM and forced exercise can neutralize this effect of MPH.
Conclusion : We conclude that forced exercise can be protective in brain against MPH-induced anxiety, depression and cognition alteration.


Pelham WE, Hoza B, Pillow DR, Gnagy EM, Kipp HL, Greiner AR, et al. Effects of methyphenidate and expectancy on children with ADHD: Behavior, academic performance, and attributions in a summer treatment program and regular classroom settings. J Consult Clin Psychol 2002;70:320-35.  Back to cited text no. 1
Challman TD, Lipsky JJ, editors. Methylphenidate: Its pharmacology and uses. Mayo Clinic Proceedings. Amsterdam, Netherlands: Elsevier; 2000.  Back to cited text no. 2
Kuczenski R, Segal DS. Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: Relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 2001;296:876-83.  Back to cited text no. 3
Teo SK, Stirling DI, Thomas SD, Khetani VD. Neurobehavioral effects of racemic threo-methylphenidate and its D and L enantiomers in rats. Pharmacol Biochem Behav 2003;74:747-54.  Back to cited text no. 4
Sandoval V, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits. J Pharmacol Exp Ther 2003;304:1181-7.  Back to cited text no. 5
Klein-Schwartz W. Abuse and toxicity of methylphenidate. Curr Opin Pediatr 2002;14:219-23.  Back to cited text no. 6
Klein-Schwartz W, McGrath J. Poison centers' experience with methylphenidate abuse in pre-teens and adolescents. J Am Acad Child Adolesc Psychiatry 2003;42:288-94.  Back to cited text no. 7
Riddle EL, Fleckenstein AE, Hanson GR. Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPS J 2006;8:E413-8.  Back to cited text no. 8
Martins MR, Reinke A, Petronilho FC, Gomes KM, Dal-Pizzol F, Quevedo J. Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res 2006;1078:189-97.  Back to cited text no. 9
Vendruscolo LF, Izídio GS, Takahashi RN, Ramos A. Chronic methylphenidate treatment during adolescence increases anxiety-related behaviors and ethanol drinking in adult spontaneously hypertensive rats. Behav Pharmacol 2008; 19:21-7.  Back to cited text no. 10
Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, et al. Therapeutic doses of oral methylphenidate significantly increases extracellular dopamine in the human brain. J Neurosci 2001;21:RC121.  Back to cited text no. 11
Bolaños CA, Willey MD, Maffeo ML, Powers KD, Kinka DW, Grausam KB, et al. Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate. Biol Psychiatry 2008;63:309-16.  Back to cited text no. 12
Salmon P. Effects of physical exercise on anxiety, depression, and sensitivity to stress: A unifying theory. Clin Psychol Rev 2001; 21:33-61.  Back to cited text no. 13
Motaghinejad M, Motevalian M, Asadi-Ghalehni M, Motaghinejad O. Attenuation of morphine withdrawal signs, blood cortisol and glucose level with forced exercise in comparison with clonidine. Adv Biomed Res 2014;3:171.  Back to cited text no. 14
[PUBMED]  Medknow Journal  
Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: Systematic review and meta-regression analysis of randomised controlled trials. BMJ 2001;322:763-7.  Back to cited text no. 15
Tomporowski PD. Effects of acute bouts of exercise on cognition. Acta Psychol (Amst) 2003;112:297-324.  Back to cited text no. 16
Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol 2006;101:1237-42.  Back to cited text no. 17
Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25:295-301.  Back to cited text no. 18
Motaghinejad M, Motaghinejad O. Preventive effects of forced exercise against alcohol induced physical dependency and reduction of pain perception threshold. Int J Prev Med 2014;10: 1299-1307.  Back to cited text no. 19
Volkow ND. Stimulant medications: How to minimize their reinforcing effects? Am J Psychiatry 2006;163:359-61.  Back to cited text no. 20
Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ. Mechanism of action of methylphenidate: Insights from PET imaging studies. J Atten Disord 2001;6(Suppl 1):S31-43.  Back to cited text no. 21
Scahill L, Carroll D, Burke K. Methylphenidate: Mechanism of action and clinical update. J Child Adolesc Psychiatr Nurs 2004;17:85-6.  Back to cited text no. 22
Ströhle A. Physical activity, exercise, depression and anxiety disorders. J Neural Transm 2009;116:777-84.  Back to cited text no. 23
Bender T, Nagy G, Barna I, Tefner I, Kádas É, Géher P. The effect of physical therapy on beta-endorphin levels. Eur J Appl Physiol 2007;100:371-82.  Back to cited text no. 24
Alaei H, Borjeian L, Azizi M, Orian S, Pourshanazari A, Hanninen O. Treadmill running reverses retention deficit induced by morphine. Eur J Pharmacol 2006;536:138-41.  Back to cited text no. 25
Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002;88:2187-95.  Back to cited text no. 26
Knaepen K, Goekint M, Heyman EM, Meeusen R. Neuroplasticity-Exercise-Induced Response of Peripheral Brain-Derived Neurotrophic Factor. Sports Med 2010;40:765-801.  Back to cited text no. 27
Volz TJ, Farnsworth SJ, King JL, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate administration alters vesicular monoamine transporter-2 function in cytoplasmic and membrane-associated vesicles. J Pharmacol Exp Ther 2007;323:738-45.  Back to cited text no. 28
Koda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T. Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice. J Neurochem 2010;114:259-70.  Back to cited text no. 29
Morton WA, Stockton GG. Methylphenidate abuse and psychiatric side effects. Prim Care Companion J Clin Psychiatry 2000;2:159-64.  Back to cited text no. 30
Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 2000;101:305-12.  Back to cited text no. 31
Dafny N, Yang PB. The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: A review of its locomotor effects. Brain Res Bull 2006;68:393-405.  Back to cited text no. 32
Kleim JA, Cooper NR, VandenBerg PM. Exercise induces angiogenesis but does not alter movement representations within rat motor cortex. Brain Res 2002;934:1-6.  Back to cited text no. 33
Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schwartz J. Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder. J Clin Psychopharmacol 2002;22:267-74.  Back to cited text no. 34
Gray JD, Punsoni M, Tabori NE, Melton JT, Fanslow V, Ward MJ, et al. Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci 2007;27:7196-207.  Back to cited text no. 35