Clinically relevant doses of methylphenidate elicit behavioral sensitization and impair cognition on drug withdrawal in normal adult rats

Sumera  Kanwal; Darakhshan Jabeen  Haleem; NaziaFeroz dr; Bushra  Ammar; Fauzia  Imtiaz

doi:10.30574/gscbps.2021.17.1.0290

Authors

Sumera Kanwal Department of Biochemistry, Liaquat National Medical College, Liaquat National Hospital and Medical College, Karachi, Pakistan.
Darakhshan Jabeen Haleem Neurochemistry and Biochemical Neuropharmacology Research Unit, Department of Biochemistry, University of Karachi, Karachi, Pakistan.
NaziaFeroz dr Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Bushra Ammar Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Fauzia Imtiaz Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.

DOI:

https://doi.org/10.30574/gscbps.2021.17.1.0290

Keywords:

Methylphenidate, Sensitization, Drug addiction, Drug withdrawal, learning and memory

Abstract

Methylphenidate (MPD), a psychostimulant, is the first line drug for improving cognitive performance in attention deficit hyperactivity disorder (ADHD). A non-prescription use of this drug for improving performance is also becoming increasingly known. A growing rise in its medical and nonmedical use suggests that the drug is addictive.The present study was designed to ascertain the reinforcing and withdrawal effects of clinically relevant doses of methylphenidate on cognitive behavior of normal adult rats. Potential addictive effects and withdrawal effects on cognition were also determined.Effects of MPD in improving cognition were monitored after drug administration as well as withdrawal using Morris Water Maze test. Taking behavioral sensitization as an important contributing factor of drug addiction; addictive effects of MPD were also determined. Data analysis was done on SPSS version 13 by one-way and two-way ANOVA (repeated measure design) where applicable; post hoc comparisons were done by Tukey’s test. Repeated oral administration of MPD (0.5 and 1mg/kg) for six days produced behavioral sensitization and reduced daily food intake. After six days of treatment rats were repeatedly administered/withdrawal from repeated administration of MPD to investigate effects of MPD on cognitive behaviors. Results showed an improvement in cognition in rats repeatedly administered with MPD (0.5 and 1 mg/kg). Whereas, withdrawal from repeated administration of MPD impaired short term memory, long term memory and memory retention. Doses of MPD which improve learning and memory are potentially addictive and elicit behavioral sensitization. Use of drug in healthy subjects can impair performance below basal levels particularly in drug withdrawal conditions.

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References

Yang PB, Swann AC, Dafny N. Acute and chronic methylphenidate dose-response assessment on three adolescent male rat strains. Brain Res Bull. 2006; 71(1-3): 301-310.

Clatworthy P, Lewis S, Brichard L, Hong Y, Izquierdo D, Clark L, et al. Dopamine release in dissociable striatal sub regions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory. J Neurosci. 2009; 29: 4690-4696.

Challman TD Lipsky JJ. Methylphenidate: its pharmacology and uses. Mayo Clin Proc. 2000; 75: 711–721.

Newcorn JH, Halperin JM. Attention-deficit disorders with oppositionality and aggression. Attention-deficit disorders and comorbidities in children, adolescents and adults. 2000; 171-208.

Pastor PN, Reuben CA. Diagnosed attention deficit hyperactivity disorder and learning disability: United States, 2004-2006. National Center for Health Statistics. Vital Health Stat. 2008; 10: 237.

Swanson JM, Volkow ND. Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD. Behav Brain Res. 2002; 130: 73–78.

Elfers CT, Roth CL. Effects of methylphenidate on weight gain and food intake in hypothalamic obesity. Front Endocrinol (Lausanne). 2011; 2: 78.

Haleem DJ, Inam Q, Haleem MA. Effects of clinically relevant doses of methyphenidate on spatial memory, behavioral sensitization and open field habituation: A time related study. Behav Brain Res. 2015; 281: 208-214.

Alam N, Najam R, Khan SS. Attenuation of methylphenidate-induced tolerance on cognition by buspirone co-administration. Pak. J. Pharm. Sci. 2015; 28(5): 1601-1605.

Wrenn CC, Heitzer AM, Roth AK, Nawrocki L, AldovinosMG.Effects of clonidine and methylphenidate on motor activity in Fmr1 knockout mice. Neurosci Letters. 2015: 585: 109-113.

Appenrodt E, Schwarzberg H. Methylphenidate-induced motor activity in rats: modulation by melatonin and vasopressin. Pharmacol Biochem Behav. 2003; 75(1): 67-73.

Wolf ME. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol. 1998; 54: 679–720.

Patrick KS, Straughn AB, Perkins JS, González MA. Evolution of stimulants to treat ADHD: transdermal methylphenidate. Hum Psychopharmacol. 2009; 24(1): 1–17.

Verster JC, Bekker EM, Kooij JJS, Buitelaar JK, Verbaten MN, Edmund R, et al. Methylphenidate significantly improves declarative memory functioning of adults with ADHD. Psychopharmacol (Berl). 2010t; 212(2): 277–281.

Cooper NJ, Keage H, Hermens D, Williams LM, Debrota D, Clark CR, et al. The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology. J Integr Neurosci. 2005; 4: 123–144.

Mehta MA, Calloway P, Sahakian BJ. Amelioration of specific working memory deficits by methylphenidate in a case of adult attention deficit/hyperactivity disorder. J Psychopharmacol. 2000; 14: 299–302.

Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci. 2000; 20: RC65

Volkow N, Swanson J. The action of enhancers can lead to addiction. Nature. 2008; 451: 520.

Markowitz JS, Logan BK, Diamond F, Patrick KS. Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". J Clin Psychopharmacol. 1999; 19(4): 362–366.

Koob GF. Addiction: Neurobiological Mechanism. Encyc Neurosci. 2009; 75-81.

Hyman SE. Addiction: a disease of learning and memory. Am J Psychiat. 2005; 162(8): 1414-1422.

Bechara A. Decision making, impulse control and loss of willpower to resist drugs: A neurocognitive perspective. Nat Neurosci. 2005; 8: 1458–1463.

Garavan H, Stout JC. Neurocognitive insights into substance abuse. Trends Cog Sci. 2005; 9: 195–201.

Paulus MP. Decision-making dysfunctions in psychiatry—altered homeostatic processing? Science. 2007; 318: 602–606.

Robbins TW, Ersche KD, Everitt BJ. Drug addiction and the memory systems of the brain. Ann New York Acad Sci. 2008; 1141: 1–21.

ChambersCD, Garavan H, Bellgrove MA. Insights into the neural basis of response inhibition from cognitive and clinical neuroscience. Neurosci Biobehav Rev. 2009; 33: 631–646.

Goldstein RZ, Craig AD, Bechara A, Garavan H, Childress AR, Paulus M, et al. The neurocircuitry of impaired insight in drug addiction. Trend Cog Sci. 2009; 13: 372–380.

Vanderschuren LJMJ, Ahmed SH. Animal Studies of Addictive Behavior. Cold Spring Harb Perspect Med. 2013; 3(4): a011932.

Salman T, Nawaz S, Ikram H, Haleem DJ. Enhancement and impairment of cognitive behaviour in Morris water maze test by methylphenidate to rats. Pak J Pharm Sci. 2019; 32(3):899-903.

Leddy JJ, Epstein LH, Jaroni JL. Influence of methylphenidate on eating in obese men. Obes Res. 2004; 12: 224–232.

Kuczenski R, Segal DS. Exposure of adolescent rats to oral methylphenidate: Preferential effects on extra cellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J. Neurosci. 2002; 22(16): 7264-7271.

Ikram H, Haleem DJ. Attenuation of Apomorphine induced sensitization by buspiron. Pharmacol Biochem Behav. 2011; 99(3): 444-450.

Orsini CA, Ginton G, Shimp KG, Avena NM, Gold MS, Setlow B. Food consumption and weight gain after cessation of chronic amphetamine administration. Appetite. 2014; 78: 76-80.

Mioranza S, Costa MS, Botton PH, Ardais AP, Matte VL, Espinosa J, et al. Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(1): 169-176.

Sprague RL, Leator SEK. Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behavior. Science. 1977; 198(4323): 1274-1276.

LeBlanc-Duchin D, Taukulis HK, Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats. Neurobiol Learn Mem. 2009; 91(3): 218-225.

Buckner RL, Petersen SE, Ojemann JG, Miezin FM, Squire LR, Raichle ME. Functional anatomical studies of explicit and implicit memory retrieval tasks. J Neuroci. 1995; 15: 12–29.

Eichenbaum H. Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron. 2004; 44(1): 109-120.

Li S, Cullen WK, Anwyl R, Rowan MJ. Dopamine-dependent facilitation of LTP induction in hippocampal CA1 by exposure to spatial novelty. Nat Neurosci. 2003; 6: 526–531.

Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiat. 2006; 60: 1111-1120.

Barrett SP, Darredeau C, BordyLE, Pihl RO. Characteristics of methylphenidate misuse in a university student sample. Can J Psychiat. 2005; 50: 457-461.

Madras BK, Miller GM, Fischman AJ.The dopamine transporter and attention-deficit/hyperactivity disorder. BiolPsychiat. 2005; 57(11): 1397-1409.

Volz TJ, Bjorklund NL, Schenk JO. Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum. Synapse. 2005; 57(3): 175-178.

Amin B, Andalib S, Vaseghi G, Mesripour A. Learning and Memory Performance After Withdrawal of Agent Abuse: A Review. Iran J Psychiat Behav Sci. 2016; 10(2): e1822.

Lukoyanov NV, Madeira MD, Paula-Barbosa MM. Behavioral and neuroanatomical consequences of chronic ethanol intake and withdrawal. Physiol Behav. 1999; 66(2): 337 -346.

Farr SA, Scherrer JF, Banks WA, Flood JF, Morley JE. Chronic ethanol consumption impairs learning and memory after cessation of ethanol. Alcohol Clin Exp Res. 2005; 29(6): 971 -982.

Cimadevilla JM, Kaminsky Y, Fenton A, Bures J. Passive and active place avoidance as a tool of spatial memory research in rats. J Neurosci Methods. 2000; 102(2): 155 -164.

Ahmadiasl N, Alipour MR, Andalib S, Ebrahimi H. Effect of ghee oil on blood fat profile and passive avoidance learning in male rats. Tabriz Uni Med Sci. 2008; 30(3): 7 -10.

Ayromlou H, Masoudian N, Ahmadi-Asl N, Habibi P, Masoudian N, Andalib S, et al. Evaluation of Chronic and Acute Effects of Gabapentin on Passive Avoidance Learning Process in Mice. J Chem Health Risks. 2014; 4(3): 33-40.

Ersche KD, Clark L, London M, Robbins TW, Sahakian BJ. Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacol. 2006; 31(5): 1036 -1047.

Herman-Stahl MA, Krebs CP, Kroutil LA, Heller DC. Risk and protective factors for nonmedical use of prescription stimulants and methamphetamine among adolescents. J Adolesc Health. 2006; 39(3): 374-380.

Swisher A, Patel A, Long K. The Effects of Acute Cocaine and Cocaine Withdrawal on Rats' Short-Term Memory Performance During Delayed Match to Sample Tasks in Y-Maze and Two-Lever Operant Paradigm. Drake University Conference on Undergraduate Research in the Sciences. 2009.

Adolphs R. Encyclopedia of Cognitive Science. 2006.

Jentsch JD, Roth RH, Taylor JR. Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drug action. Prog Brain Res. 2000; 126: 433-453.

Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med. 1998; 49: 173-184.

Gulya K, Grant KA, Valverius P, Hoffman PL, Tabakoff B. Brain regional specificity and time-course of changes in the NMDA receptor-ionophore complex during ethanol withdrawal. Brain Res. 1991; 547(1): 129 -134.

Kril JJ, Halliday GM, Svoboda MD, Cartwright H. The cerebral cortex is damaged in chronic alcoholics. Neurosci. 1997; 79(4): 983 -998.

Lack AK, Diaz MR, Chappell A, DuBois DW, McCool BA. Chronic ethanol and withdrawal differentially modulate pre- and postsynaptic function at glutamatergic synapses in rat basolateral amygdala. J Neurophysiol. 2007; 98(6): 3185 -3196.

Little HJ, Croft AP, O'Callaghan MJ, Brooks SP, Wang G, Shaw SG. Selective increases in regional brain glucocorticoid: a novel effect of chronic alcohol. Neurosci. 2008; 156(4): 1017-1027.

Morley JE. The endocrinology of the opiates and opioid peptides. Metabolism. 1981; 30(2): 195 -209.