Chronic oral methylphenidate treatment reversibly increases striatal dopamine transporter and dopamine type 1 receptor binding in rats

Abstract

Previously, we created an 8-h limited-access dual bottle drinking paradigm to deliver methylphenidate (MP) to rats at two dosages that result in a pharmacokinetic profile similar to patients treated for attention deficit hyperactivity disorder. Chronic treatment resulted in altered behavior, with some effects persisting beyond treatment. In the current study, adolescent male Sprague–Dawley rats were split into three groups at four weeks of age: control (water), low-dose MP (LD), and high-dose MP (HD). Briefly, 4 mg/kg (low dose; LD) or 30 mg/kg (high dose; HD) MP was consumed during the first hour, and 10 mg/kg (LD) or 60 mg/kg (HD) MP during hours two through eight. Following three months of treatment, half of the rats in each group (n = 8–9/group) were euthanized, and remaining rats went through a 1-month abstinence period, then euthanized. In vitro receptor autoradiography was performed to quantify binding levels of dopamine transporter (DAT), dopamine type 1 (D1R)-like receptors, and dopamine type 2 (D2R)-like receptors using [3H] WIN35,428, [3H] SCH23390, and [3H] Spiperone, respectively. Immediately following treatment, HD MP-treated rats had increased DAT and D1R-like binding in several subregions of the basal ganglia, particularly more caudal portions of the caudate putamen, which correlated with some previously reported behavioral changes. There were no differences between treatment groups in any measure following abstinence. These findings suggest that chronic treatment with a clinically relevant high dose of MP results in reversible changes in dopamine neurochemistry, which may underlie some effects on behavior.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Beveridge TJ, Smith HR, Nader MA, Porrino LJ (2009) Abstinence from chronic cocaine self-administration alters striatal dopamine systems in rhesus monkeys. Neuropsychopharmacology 34:1162–1171

    CAS  Article  PubMed  Google Scholar 

  2. Biederman J, Monuteaux MC, Spencer T, Wilens TE, MacPherson HA, Faraone SV (2008) Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry 165:597–603

    Article  PubMed  Google Scholar 

  3. Bogle KE, Smith BH (2009) Illicit methylphenidate use: a review of prevalence, availability, pharmacology, and consequences Curr Drug Abuse Rev 2:157–176

  4. Brandon CL, Marinelli M, Baker LK, White FJ (2001) Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology 25:651–661

    CAS  Article  PubMed  Google Scholar 

  5. Brandon CL, Marinelli M, White FJ (2003) Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons. Biol Psychiatry 54:1338–1344

    CAS  Article  PubMed  Google Scholar 

  6. Bymaster FP et al (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711

    CAS  Article  PubMed  Google Scholar 

  7. Carlezon WA Jr, Mague SD, Andersen SL (2003) Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry 54:1330–1337. doi:10.1016/j.biopsych.2003.08.020

    CAS  Article  PubMed  Google Scholar 

  8. Coulter CL, Happe HK, Murrin LC (1997) Dopamine transporter development in postnatal rat striatum: an autoradiographic study with [3 H] WIN 35,428. Dev Brain Res 104:55–62

    CAS  Article  Google Scholar 

  9. Dahl RE (2004) Adolescent brain development: a period of vulnerabilities and opportunities. Keynote Address Ann NY Acad Sci 1021:1–22

    Article  PubMed  Google Scholar 

  10. DeLong MR, Georgopoulos AP (2011) Motor functions of the basal ganglia. In: Comprehensive physiology. Wiley, New York. doi:10.1002/cphy.cp010221

  11. Eilam D, Clements KV, Szechtman H (1991) Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats. Behav Brain Res 45:117–124

    CAS  Article  PubMed  Google Scholar 

  12. Elkins IJ, McGue M, Iacono WG (2007) Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 64:1145–1152

    Article  PubMed  Google Scholar 

  13. Fone KCF, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents—relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102. doi:10.1016/j.neubiorev.2008.03.003

    CAS  Article  PubMed  Google Scholar 

  14. Gatley SJ, Volkow ND, Gifford AN, Fowler JS, Dewey SL, Ding Y-S, Logan J (1999) Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans. Psychopharmacology 146:93–100

    CAS  Article  PubMed  Google Scholar 

  15. Gerasimov MR et al (2000) Comparison between intraperitoneal and oral methylphenidate administration: a microdialysis and locomotor activity study. J Pharmacol Exp Ther 295:51–57

    CAS  PubMed  Google Scholar 

  16. Giedd JN et al (2008) Trajectories of anatomic brain development as a phenotype. Novartis Found Symp 289:101–112 (discussion 112-108, 193-105)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Gill KE, Beveridge T, Porrino LJ (2012) Interaction of environment and chronic methylphenidate on anxiety-like behavior and dopamine receptors in adolescent rodents. FASEB J 26(844):846

    Google Scholar 

  18. Grant BF, Dawson DA (1997) Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: results from the national longitudinal alcohol epidemiologic survey. J Subst Abuse 9:103–110

    CAS  Article  PubMed  Google Scholar 

  19. Gray JD et al (2007) Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci 27:7196–7207

    CAS  Article  PubMed  Google Scholar 

  20. Greenhill LL et al (2002) Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 41:26S–49S

    Article  PubMed  Google Scholar 

  21. Halberda JP, Middaugh LD, Gard BE, Jackson BP (1997) DAD1-and DAD2-like agonist effects on motor activity of C57 mice: differences compared to rats. Synapse 26:81–92

    CAS  Article  PubMed  Google Scholar 

  22. Howes SR, Dalley JW, Morrison CH, Robbins TW, Everitt BJ (2000) Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression. Psychopharmacology 151:55–63. doi:10.1007/s002130000451

    CAS  Article  PubMed  Google Scholar 

  23. Imperato A, Mele A, Scrocco MG, Puglisi-Allegra S (1992) Chronic cocaine alters limbic extracellular dopamine. Neurochem Basis Addict Eur J Pharmacol 212:299–300

    CAS  Google Scholar 

  24. Imperato A, Obinu MC, Carta G, Mascia MS, Casu MA, Gessa GL (1996) Reduction of dopamine release and synthesis by repeated amphetamine treatment: role in behavioral sensitization. Eur J Pharmacol 317:231–237

    CAS  Article  PubMed  Google Scholar 

  25. Isovich E, Engelmann M, Landgraf R, Fuchs E (2001) Social isolation after a single defeat reduces striatal dopamine transporter binding in rats. Eur J Neurosci 13:1254–1256. doi:10.1046/j.0953-816x.2001.01492.x

    CAS  Article  PubMed  Google Scholar 

  26. Izenwasser S, Coy AE, Ladenheim B, Loeloff RJ, Cadet JL, French D (1999) Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Eur J Pharmacol 373:187–193. doi:10.1016/S0014-2999(99)00274-5

    CAS  Article  PubMed  Google Scholar 

  27. Jones GH, Marsden CA, Robbins TW (1990) Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens. Psychopharmacology 102:364–372. doi:10.1007/BF02244105

    CAS  Article  PubMed  Google Scholar 

  28. King MV, Seeman P, Marsden CA, Fone KCF (2009) Increased dopamine D 2High receptors in rats reared in social isolation. Synapse 63:476–483. doi:10.1002/syn.20624

    CAS  Article  PubMed  Google Scholar 

  29. 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 Ther 296:876–883

    CAS  PubMed  Google Scholar 

  30. Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22:7264–7271

    CAS  PubMed  Google Scholar 

  31. Kuczenski R, Segal DS (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57:1391–1396

    CAS  Article  PubMed  Google Scholar 

  32. Letchworth SR, Nader MA, Smith HR, Friedman DP, Porrino LJ (2001) Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys. J Neurosci 21:2799–2807

    CAS  PubMed  Google Scholar 

  33. Little KY et al (1998) Brain dopamine transporter messenger RNA and binding sites in cocaine users: a postmortem study. Arch Gen Psychiatry 55:793–799

    CAS  Article  PubMed  Google Scholar 

  34. Mannuzza S, Klein RG, Truong NL, Moulton III JL, Roizen ER, Howell KH, Castellanos FX (2008) Age of methylphenidate treatment initiation in children with ADHD and later substance abuse: prospective follow-up into adulthood. Am J Psychiatry 165(5):604–609. doi:10.1176/appi.ajp.2008.07091465

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S (2002) Dopamine transport function is elevated in cocaine users. J Neurochem 81:292–300

    CAS  Article  PubMed  Google Scholar 

  36. McCabe SE, Knight JR, Teter CJ, Wechsler H (2005) Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction 100:96–106

    Article  PubMed  Google Scholar 

  37. McCabe SE, Teter CJ, Boyd CJ (2006) Medical use, illicit use and diversion of prescription stimulant medication. J Psychoact Drugs 38:43–56

    Article  Google Scholar 

  38. Mick E, Faraone SV, Biederman J (2004) Age-dependent expression of attention-deficit/hyperactivity disorder symptoms. Psychiatr Clin North Am 27:215–224. doi:10.1016/j.psc.2004.01.003

    Article  PubMed  Google Scholar 

  39. Nader MA et al (2002) Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology 27:35–46

    CAS  Article  PubMed  Google Scholar 

  40. Parsons L, Smith A, Justice J (1991) Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine. Synapse 9:60–65

    CAS  Article  PubMed  Google Scholar 

  41. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, New York

    Google Scholar 

  42. Randall S, Hannigan J (1999) In utero alcohol and postnatal methylphenidate: locomotion and dopamine receptors. Neurotoxicol Teratol 21:587–593

    CAS  Article  PubMed  Google Scholar 

  43. Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533 (sc271_5_1835 [pii])

    Article  PubMed  PubMed Central  Google Scholar 

  44. Robertson MW, Leslie CA, Bennett JP (1991) Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment. Brain Res 538:337–339

    CAS  Article  PubMed  Google Scholar 

  45. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291. doi:10.1016/0165-0173(93)90013-P

    CAS  Article  PubMed  Google Scholar 

  46. Schlussman SD, Zhang Y, Kane S, Stewart CL, Ho A, Kreek MJ (2003) Locomotion, stereotypy, and dopamine D1 receptors after chronic “binge” cocaine in C57BL/6 J and 129/J mice. Pharmacol Biochem Behav 75:123–131. doi:10.1016/S0091-3057(03)00067-4

    CAS  Article  PubMed  Google Scholar 

  47. Segal DS, Kuczenski R (1992) Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens. Brain Res 577:351–355

    CAS  Article  PubMed  Google Scholar 

  48. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463 (S0149-7634(00)00014-2 [pii])

    CAS  Article  PubMed  Google Scholar 

  49. Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365. doi:10.1124/pr.109.001933

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Takakusaki K, Saitoh K, Harada H, Kashiwayanagi M (2004) Role of basal ganglia–brainstem pathways in the control of motor behaviors. Neurosci Res 50:137–151

    CAS  Article  PubMed  Google Scholar 

  51. Tarazi FI, Florijn WJ, Creese I (1997) Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment. Neuroscience 78:985–996. doi:10.1016/S0306-4522(96)00631-8

    CAS  Article  PubMed  Google Scholar 

  52. Tarazi FI, Campbell A, Yeghiayan SK, Baldessarini RJ (1998) Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D1-, D2- and D4-like receptors. Neuroscience 83:169–176. doi:10.1016/S0306-4522(97)00386-2

    CAS  Article  PubMed  Google Scholar 

  53. Tarazi FI, Tomasini EC, Baldessarini RJ (1999) Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: an autoradiographic study. Dev Neurosci 21:43–49. doi:10.1159/000017365

    CAS  Article  PubMed  Google Scholar 

  54. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (2006) Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy 26:1501–1510. doi:10.1592/phco.26.10.1501

    Article  PubMed  PubMed Central  Google Scholar 

  55. Thanos PK, Michaelides M, Benveniste H, Wang GJ, Volkow ND (2007) Effects of chronic oral methylphenidate on cocaine self-administration and striatal dopamine D2 receptors in rodents. Pharmacol Biochem Behav 87:426–433

    CAS  Article  PubMed  Google Scholar 

  56. Thanos PK et al (2015) A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior. Pharmacol Biochem Behav 131:143–153

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Thompson D, Martini L, Whistler JL (2010) Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine. PLoS One 5:e11038

    Article  PubMed  PubMed Central  Google Scholar 

  58. Visser SN et al (2014) Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003–2011. J Am Acad Child Adolesc Psychiatry 53(34–46):e32. doi:10.1016/j.jaac.2013.09.001

    Google Scholar 

  59. Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386(6627):827–830

    CAS  Article  PubMed  Google Scholar 

  60. Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ (2002) Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies. Eur Neuropsychopharmacol 12:557–566 (S0924977X02001049 [pii])

    CAS  Article  PubMed  Google Scholar 

  61. Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Hitzemann R, Pappas N (1998) Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155(10):1325–1331

    CAS  Article  PubMed  Google Scholar 

  62. Volkow ND et al (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21:RC121

    CAS  PubMed  Google Scholar 

  63. Wang G-J et al (2013) Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder. PLoS One 8:e63023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Wilens TE, Faraone SV, Biederman J, Gunawardene S (2003) Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111:179–185

    Article  PubMed  Google Scholar 

  65. Wilens T et al (2008) Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry 47:21–31

    Article  PubMed  Google Scholar 

  66. Wilson JM et al (1994) Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. J Neurosci 14:2966–2979

    CAS  PubMed  Google Scholar 

  67. Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl− -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21–55 (S0163-7258(01)00158-9 [pii])

    CAS  Article  PubMed  Google Scholar 

  68. Zakharova E, Miller J, Unterwald E, Wade D, Izenwasser S (2009) Social and physical environment alter cocaine conditioned place preference and dopaminergic markers in adolescent male rats. Neuroscience 163:890–897. doi:10.1016/j.neuroscience.2009.06.068

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Zhang Y, Loonam TM, NOAILLES PA, Angulo JA (2001) Comparison of cocaine-and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic, and early withdrawal conditions. Ann NY Acad Sci 937:93–120

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the New York Research Foundation [Q0942016] and the National Institute of Health [R01HD70888].

Author information

Affiliations

Authors

Corresponding author

Correspondence to Panayotis K. Thanos.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Robison, L.S., Ananth, M., Hadjiargyrou, M. et al. Chronic oral methylphenidate treatment reversibly increases striatal dopamine transporter and dopamine type 1 receptor binding in rats. J Neural Transm 124, 655–667 (2017). https://doi.org/10.1007/s00702-017-1680-4

Download citation

Keywords

  • Methylphenidate
  • Psychostimulant
  • Dopamine
  • Transporter
  • Reward deficiency syndrome, reward, addiction