Abstract
Methylphenidate (MPD) is a psychostimulant that is widely prescribed to treat attention deficit-hyperactivity disorder, but it is abused recreationally as well. The nucleus accumbens (NAc) is part of the motivation circuit implicated in drug-seeking behaviors. The NAc neuronal activity was recorded alongside the behavioral activity from young and adult rats to determine if there are significant differences in the response to MPD. The same dose of MPD elicits behavioral sensitization in some animals and behavioral tolerance in others. In adult animals, higher doses of MPD resulted in a greater ratio of tolerance/sensitization. Animals who responded to chronic MPD with behavioral sensitization usually exhibited further increases in their NAc neuronal firing rates as well. Different upregulations of transcription factors (ΔFOSB/CREB), variable proportions of D1/D2 dopamine receptors, and modulation from other brain areas may predispose certain animals to express behavioral and neuronal sensitization versus tolerance to MPD.
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References
Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA (2002) Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nat Neurosci 5(1):13–14. https://doi.org/10.1038/nn777
Arria AM, Wish ED (2006) Nonmedical use of prescription stimulants among students. Pediatr Ann 35(8):565–571. https://doi.org/10.3928/0090-4481-20060801-09
Askenasy EP, Taber KH, Yang PB, Dafny N (2007) Methylphenidate (ritalin): behavioral studies in the rat. Int J Neurosci 117(6):757–794. https://doi.org/10.1080/00207450600910176
Blakemore S, Burnett S, Dahl RE (2010) The role of puberty in the developing adolescent brain. Hum Brain Mapp 31(6):926–933. https://doi.org/10.1002/hbm.21052
Brandon CL, Marinelli M, Baker LK, White FJ (2001) Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology 25(5):651–661. https://doi.org/10.1016/S0893-133X(01)00281-0
Brenhouse HC, Andersen SL (2011) Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes. Neurosci Biobehav Rev 35(8):1687–1703. https://doi.org/10.1016/j.neubiorev.2011.04.013
Broussard E, Reyes-Vazquez C, Dafny N (2019) Methylphenidate dose–response behavioral and neurophysiological study of the ventral tegmental area and nucleus accumbens in adolescent rats. Eur J Neurosci 50(4):2635–2652. https://doi.org/10.1111/ejn.14402
Casey BJ, Getz S, Galvan A (2008) The adolescent brain. Dev Rev 28(1):62–77. https://doi.org/10.1016/j.dr.2007.08.003
Chao J, Nestler EJ (2004) Molecular neurobiology of drug addiction. Annu Rev Med 55(1):113–132. https://doi.org/10.1146/annurev.med.55.091902.103730
Chemali JJ, Van CJ, Brown EN, Solt K (2012) Active emergence from propofol general anesthesia is induced by methylphenidate. Anesthesiology 116(5):998–1005. https://doi.org/10.1097/ALN.0b013e3182518bfc
Chong SL, Claussen CM, Dafny N (2012) Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration. Brain Res Bull 87(4):445–456. https://doi.org/10.1016/j.brainresbull.2012.01.004
Claussen C, Dafny N (2011) Acute and chronic methylphenidate modulates the neuronal activity of the caudate nucleus recorded from freely behaving rats. Brain Res Bull 87(4):387–396. https://doi.org/10.1016/j.brainresbull.2011.10.008
Claussen CM, Chong SL, Dafny N (2012) Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects. Pharmacol Biochem Behav 101(2):208–216. https://doi.org/10.1016/j.pbb.2012.01.002
Claussen CM, Chong SL, Dafny N (2014) Nucleus accumbens neuronal activity correlates to the animal’s behavioral response to acute and chronic methylphenidate. Physiol Behav 129:85–94. https://doi.org/10.1016/j.physbeh.2014.02.024
Claussen CM, Witte LJ, Dafny N (2015) Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect. J Exp Pharmacol 7:1–9. https://doi.org/10.2147/jep.s75300
Dafny N, Yang PB (2006) The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects. Brain Res Bull 68(6):393–405. https://doi.org/10.1016/j.brainresbull.2005.10.005
Dietz P, Striegel H, Franke AG, Lieb K, Simon P, Ulrich R (2013) Randomized response estimates for the 12-month prevalence of cognitive-enhancing drug use in university students. Pharmacotherapy 33(1):44–50. https://doi.org/10.1002/phar.1166
Eckermann K, Beasley A, Yang P, Gaytan O, Swann A, Dafny N (2001) Methylphenidate sensitization is modulated by valproate. Life Sci 69(1):47–57. https://doi.org/10.1016/S0024-3205(01)01095-5
Faraone SV (2018) The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev 87:255–270. https://doi.org/10.1016/j.neubiorev.2018.02.001
Florence S, King N, Carasco A, Dafny N (2020) Glutamate and dopamine in the VTA participate differently in the acute and chronic effects of methylphenidate. Behav Brain Res 380:17–25
Frolov A, Reyes-Vasquez C, Dafny N (2015) Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate. J Neurophysiol 113(1):369–379. https://doi.org/10.1152/jn.00633.2013
Galvan A, Hare TA, Parra CE, Penn J, Voss H, Glover G, Casey BJ (2006) Earlier development of the accumbens relative to orbitofrontal cortex might underlie risk-taking behavior in adolescents. J Neurosci 26(25):6885–6892. https://doi.org/10.1523/JNEUROSCI.1062-06.2006
Gatley SJ, Volkow ND, Gifford AN, Fowler JS, Dewey SL, Ding Y, Logan J (1999) Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans. Psychopharmacology 146(1):93–100. https://doi.org/10.1007/s002130051093
Gaytan O, Ghelani D, Martin S, Swann A, Dafny N (1997) Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat. Brain Res 777(1):1–12. https://doi.org/10.1016/S0006-8993(97)00880-9
Gaytan O, Nason R, Alagugurusamy R, Swann A, Dafny N (2000) MK-801 blocks the development of sensitization to the locomotor effects of methylphenidate. Brain Res Bull 51(6):485–492. https://doi.org/10.1016/S0361-9230(99)00268-3
Greengard P (2001) The neurobiology of dopamine signaling. Biosci Rep 21(3):247–269. https://doi.org/10.1023/A:1013205230142
Harris J, Sahakian B, Kessler RC, Gazzaniga M, Farah MJ, Greely H, Campbell P (2008) Towards responsible use of cognitive-enhancing drugs by the healthy. Nature 456(7223):702–705. https://doi.org/10.1038/456702a
Hyman SE, Malenka RC (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2(10):695–703. https://doi.org/10.1038/35094560
Ikemoto S, Yang C, Tan A (2015) Basal ganglia circuit loops, dopamine and motivation: a review and enquiry. Behav Brain Res 290:17–31. https://doi.org/10.1016/j.bbr.2015.04.018
Imbert B, Labrune N, Lancon C, Simon N (2014) Use of extended-release methylphenidate (concerta) in treatment of cocaine dependence in a patient presenting with attention deficit hyperactivity disorder. J Neuropsychiatry Clin Neurosci 26(3):E49–E50. https://doi.org/10.1176/appi.neuropsych.13080194
Jernigan TL, Toga AW, Sowell ER, Thompson PM, Holmes CJ (1999) In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nat Neurosci 2(10):859–861. https://doi.org/10.1038/13154
Jones Z, Dafny N (2014) Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior. J Neural Transm 121(3):327–345. https://doi.org/10.1007/s00702-013-1101-2
Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10(8):561–572. https://doi.org/10.1038/nrn2515
Kelley AE, Domesick VB, Nauta WJH (1982) The amygdalostriatal projection in the rat—an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7(3):615–630. https://doi.org/10.1016/0306-4522(82)90067-7
Kharas N, Reyes-Vazquez C, Dafny N (2017) Locus coeruleus neuronal activity correlates with behavioral response to acute and chronic doses of methylphenidate (ritalin) in adolescent rats. J Neural Transm 124(10):1239–1250. https://doi.org/10.1007/s00702-017-1760-5
Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009) Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens. Proc Natl Acad Sci USA 106(8):2915–2920. https://doi.org/10.1073/pnas.0813179106
Kim MG, Kim J, Kim SC, Jeong J (2020) Twitter analysis of the nonmedical use and side effects of methylphenidate: machine learning study. J Med Internet Res 22(2). https://doi.org/10.2196/16466
King N, Floren S, Kharas N, Thomas M, Dafny N (2019) Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate. Pharmacol Biochem Behav 184:172737. https://doi.org/10.1016/j.pbb.2019.172737
Kita H, Kitai ST (1990) Amygdaloid projections to the frontal cortex and the striatum in the rat. J Comp Neurol 298(1):40–49. https://doi.org/10.1002/cne.902980104
Kollins SH, MacDonald EK, Rush CR (2001) Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review. Pharmacol Biochem Behav 68(3):611–627. https://doi.org/10.1016/S0091-3057(01)00464-6
Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Therap 296(3):876–883
Lee SH, Seo WS, Sung HM, Choi TY, Kim SY, Choi S, Lee JH (2012) Effect of methylphenidate on sleep parameters in children with ADHD. Psychiatry Investig 9(4):384–390. https://doi.org/10.4306/pi.2012.9.4.384
Li Y, Kolb B, Robinson TE (2003) The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen. Neuropsychopharmacology 28(6):1082–1085. https://doi.org/10.1038/sj.npp.1300115
Marco EM, Adriani W, Ruocco LA, Canese R, Sadile AG, Laviola G (2011) Neurobehavioral adaptations to methylphenidate: the issue of early adolescent exposure. Neurosci Biobehav Rev 35(8):1722–1739. https://doi.org/10.1016/j.neubiorev.2011.02.011
McClung CA, Nestler EJ, Zachariou V (2005) Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J Neurosci 25(25):6005–6015. https://doi.org/10.1523/JNEUROSCI.0062-05.2005
McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21(21):8655–8663. https://doi.org/10.1523/JNEUROSCI.21-21-08655.2001
Ming T, Dafny N (2021) Glutaminergic signaling in the nucleus accumbens modulate the behavioral response to acute and chronic methylphenidate. J Exp Neurol 2:49–61
Nestler EJ (2012) Transcriptional mechanisms of drug addiction. Clin Psychopharmacol Neurosci 10(3):136–143. https://doi.org/10.9758/cpn.2012.10.3.136
Patrick KS, Markowitz JS (1997) Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder. Hum Psychopharmacol 12(6):527–546. https://doi.org/10.1002/(SICI)1099-1077(199711/12)12:6%3c527::AID-HUP932%3e3.0.CO;2-U
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates
Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Elsevier B.V. https://doi.org/10.1016/S0165-0173(97)00021-0
Podet A, Lee MJ, Swann AC, Dafny N (2010) Nucleus accumbens lesions modulate the effects of methylphenidate. Brain Res Bull 82(5):293–301. https://doi.org/10.1016/j.brainresbull.2010.05.006
Reppucci C, Petrovich G (2016) Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats. Brain Struct Funct 221(6):2937–2962. https://doi.org/10.1007/s00429-015-1081-0
Ririe D, Ririe K, Sethna N, Fox L (1997) Unexpected interaction of methylphenidate (ritalin®) with anaesthetic agents. Pediatr Anesth 7(1):69–72. https://doi.org/10.1046/j.1460-9592.1997.d01-34.x
Ruffle JK (2014) Molecular neurobiology of addiction: what’s all the (Δ)FosB about? Am J Drug Alcohol Abuse 40(6):428–437. https://doi.org/10.3109/00952990.2014.933840
Safer DJ (2016) Recent trends in stimulant usage. J Atten Disord 20(6):471–477. https://doi.org/10.1177/1087054715605915
Salek RL, Claussen CM, Pérez A, Dafny N (2012) Acute and chronic methylphenidate alters prefrontal cortex neuronal activity recorded from freely behaving rats. Eur J Pharmacol 679(1–3):60–67
Sherwood NM, Timiras PS (1970) Aoe stereotaxic atlas of the developing rat brain. University of California Press, Berkeley
Solt K, Cotten JF, Cimenser A, Wong KFK, Chemali JJ, Brown EN (2011) Methylphenidate actively induces emergence from general anesthesia. Anesthesiology 115(4):791–803. https://doi.org/10.1097/ALN.0b013e31822e92e5
Stix G (2009) Turbocharging the brain. Sci Am 301(4)
Swanson J, Baler RD, Volkow ND (2011) Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress. Neuropsychopharmacology 36(1):207–226. https://doi.org/10.1038/npp.2010.160
Tu G, Ying L, Ye L, Zhao J, Liu N, Li J, Zhang L (2019) Dopamine D1 and D2 receptors differentially regulate Rac1 and Cdc42 signaling in the nucleus accumbens to modulate behavioral and structural plasticity after repeated methamphetamine treatment. Biol Psychiatry 86(11):820
Venkataraman SS, Claussen C, Joseph M, Dafny N (2017) Concomitant behavioral and PFC neuronal activity recorded following dose-response protocol of MPD in adult male rats. Brain Res Bull 130:125–137. https://doi.org/10.1016/j.brainresbull.2017.01.008
Venkataraman SS, Joseph M, Dafny N (2019) Concomitant behavioral and prefrontal cortex neuronal responses following acute and chronic methylphenidate exposure in adolescent and adult rats. Brain Res Bull 144:200–212. https://doi.org/10.1016/j.brainresbull.2018.11.004
Venkataraman SS, Claussen CM, Kharas N, Dafny N (2020) The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (ritalin). concomitant behavioral and neuronal recording study. Brain Res Bull 157:77–89. https://doi.org/10.1016/j.brainresbull.2019.10.009
Verghese C, Abdijadid S (2021) Methylphenidate. StatPearls. Retrieved from https://pubmed.ncbi.nlm.nih.gov/29494058/
Volkow ND, Swanson JM (2008) Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood? Am J Psychiatry 165(5):553–555. https://doi.org/10.1176/appi.ajp.2008.08020237
Volkow ND, Ding Y, Fowler JS, Wang G, Logan J, Gatley JS, Wolf AP (1995) Is methylphenidate like cocaine?: Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 52(6):456–463. https://doi.org/10.1001/archpsyc.1995.03950180042006
Volkow ND, Wang G, Fowler JS, Thanos P, Logan J, Gatley SJ, Pappas N (2002) Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study. Synapse 46(2):79–82. https://doi.org/10.1002/syn.10137
Wanchoo SJ, Lee MJ, Swann AC, Dafny N (2009) Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate. Brain Res 1312:89–100. https://doi.org/10.1016/j.brainres.2009.11.035
Weikop P, Yoshitake T, Kehr J (2007) Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain. Eur Neuropsychopharmacol 17(10):658–671. https://doi.org/10.1016/j.euroneuro.2007.02.014
Wise RA (1996) Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19(1):319–340. https://doi.org/10.1146/annurev.ne.19.030196.001535
Yang PB, Swann AC, Dafny N (2007) Methylphenidate treated at the test cage—dose-dependent sensitization or tolerance depend on the behavioral assay used. Crit Rev Neurobiol 19(1):59–77. https://doi.org/10.1615/CritRevNeurobiol.v19.i1.20
Yang PB, Cuellar DO, Swann AC, Dafny N (2011) Age and genetic strain differences in response to chronic methylphenidate administration. Behav Brain Res 218(1):206–217. https://doi.org/10.1016/j.bbr.2010.11.034
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The author like to appreciate John Concha for the figures preparation and NIH NIDA RO1 DA027222 Grant.
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Medina, A.C., Kabani, A., Reyes-Vasquez, C. et al. Age differences to methylphenidate-NAc neuronal and behavioral recordings from freely behaving animals. J Neural Transm 129, 1061–1076 (2022). https://doi.org/10.1007/s00702-022-02526-0
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DOI: https://doi.org/10.1007/s00702-022-02526-0