Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD

Abstract

Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.

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References

  1. 1.

    Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, Faraone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Walters EE, Zaslavsky AM (2006) The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 163(4):716–723

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164(6):942–948

    Article  PubMed  Google Scholar 

  3. 3.

    Biederman J, Petty CR, Clarke A, Lomedico A, Faraone SV (2011) Predictors of persistent ADHD: an 11-year follow-up study. J Psychiatr Res 45(2):150–155

    Article  PubMed  Google Scholar 

  4. 4.

    Biederman J, Petty CR, Evans M, Small J, Faraone SV (2010) How persistent is ADHD? A controlled 10-year follow-up study of boys with ADHD. Psychiatry Res 177(3):299–304

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    De Sousa A, Kalra G (2012) Drug therapy of attention deficit hyperactivity disorder: current trends. Mens Sana Monogr 10(1):45–69

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Collins RJ, Weeks JR, Cooper MM, Good PI, Russell RR (1984) Prediction of abuse liability of drugs using IV self-administration by rats. Psychopharmacology 82(1–2):6–13

    CAS  PubMed  Google Scholar 

  7. 7.

    Fredericks EM, Kollins SH (2004) Assessing methylphenidate preference in ADHD patients using a choice procedure. Psychopharmacology 175(4):391–398

    CAS  PubMed  Google Scholar 

  8. 8.

    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(1):179–185

    Article  PubMed  Google Scholar 

  9. 9.

    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

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Kollins SH (2008) A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders. Curr Med Res Opin 24(5):1345–1357

    Article  PubMed  Google Scholar 

  11. 11.

    Harvey RC, Sen S, Deaciuc A, Dwoskin LP, Kantak KM (2011) Methylphenidate treatment in adolescent rats with an attention deficit/hyperactivity disorder phenotype: cocaine addiction vulnerability and dopamine transporter function. Neuropsychopharmacology 36(4):837–847

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Cascade E, Kalali AH, Wigal SB (2010) Real-world data on: attention deficit hyperactivity disorder medication side effects. Psychiatry 7(4):13–15

    PubMed  Google Scholar 

  13. 13.

    Russell VA (2001) Increased AMPA receptor function in slices containing the prefrontal cortex of spontaneously hypertensive rats. Metab Brain Dis 16(3–4):143–149

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Lehohla M, Kellaway L, Russell VA (2004) NMDA receptor function in the prefrontal cortex of a rat model for attention-deficit hyperactivity disorder. Metab Brain Dis 19(1–2):35–42

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Warton FL, Howells FM, Russell VA (2009) Increased glutamate-stimulated release of dopamine in substantia nigra of a rat model for attention-deficit/hyperactivity disorder-lack of effect of methylphenidate. Metab Brain Dis 24(4):599–613

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Miller EM, Pomerleau F, Huettl P, Gerhardt GA, Glaser PE (2014). Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology 231(15):3019–3029

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Burmeister JJ, Davis VA, Quintero JE, Pomerleau F, Huettl P, Gerhardt GA (2013) Glutaraldehyde cross-linked glutamate oxidase coated microelectrode arrays: selectivity and resting levels of glutamate in the CNS. ACS Chem Neurosci 4(5):721–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Rutherford EC, Pomerleau F, Huettl P, Stromberg I, Gerhardt GA (2007) Chronic second-by-second measures of L-glutamate in the central nervous system of freely moving rats. J Neurochem 102(3):712–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hascup KN, Hascup ER, Stephens ML, Glaser PE, Yoshitake T, Mathe AA, Gerhardt GA, Kehr J (2011) Resting glutamate levels and rapid glutamate transients in the prefrontal cortex of the flinders sensitive line rat: a genetic rodent model of depression. Neuropsychopharmacology 36(8):1769–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hinzman JM, Thomas TC, Burmeister JJ, Quintero JE, Huettl P, Pomerleau F, Gerhardt GA, Lifshitz J (2010) Diffuse brain injury elevates tonic glutamate levels and potassium-evoked glutamate release in discrete brain regions at two days post-injury: an enzyme-based microelectrode array study. J Neurotrauma 27(5):889–899

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Paxinos G, Watson C (2009). The rat brain in stereotaxic coordinates. Academic Press/Elsevier, Amsterdam

    Google Scholar 

  22. 22.

    Swanson JM, Volkow ND (2002) Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD. Behav Brain Res 130(1–2):73–78

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Kuczenski R, Segal DS (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57(11):1391–1396

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Wargin W, Patrick K, Kilts C, Gualtieri CT, Ellington K, Mueller RA, Kraemer G, Breese GR (1983) Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther 226(2):382–386

    CAS  PubMed  Google Scholar 

  25. 25.

    Jensen GB, Collier GH, Medvin MB (1983) A cost-benefit analysis of nocturnal feeding in the rat. Physiol Behav 31(4):555–559

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    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(3):876–883

    CAS  PubMed  Google Scholar 

  27. 27.

    Mc Fie S, Sterley TL, Howells FM, Russell VA (2012) Clozapine decreases exploratory activity and increases anxiety-like behaviour in the Wistar-Kyoto rat but not the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Brain Res 1467:91–103

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    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(16):7264–7271

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Johansen EB, Sagvolden T, Kvande G (2005) Effects of delayed reinforcers on the behavior of an animal model of attention-deficit/hyperactivity disorder (ADHD). Behav Brain Res 162(1):47–61

    Article  PubMed  Google Scholar 

  30. 30.

    Howells FM, Bindewald L, Russell VA (2009) Cross-fostering does not alter the neurochemistry or behavior of spontaneously hypertensive rats. Behav Brain Funct 5:24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yang PB, Amini B, Swann AC, Dafny N (2003) Strain differences in the behavioral responses of male rats to chronically administered methylphenidate. Brain Res 971(2):139–152

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Amini B, Yang PB, Swann AC, Dafny N (2004) Differential locomotor responses in male rats from three strains to acute methylphenidate. Int J Neurosci 114(9):1063–1084

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Knardahl S, Sagvolden T (1981) Regarding hyperactivity of the SHR in the open-field test. Behav Neural Biol 32(2):274–275

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Sagvolden T, Pettersen MB, Larsen MC (1993) Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains. Physiol Behav 54(6):1047–1055

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Pulvirenti L, Swerdlow NR, Koob GF (1989) Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats. Neurosci Lett 103(2):213–218

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Pulvirenti L, Swerdlow NR, Koob GF (1991) Nucleus accumbens NMDA antagonist decreases locomotor activity produced by cocaine, heroin or accumbens dopamine, but not caffeine. Pharmacol Biochem Behav 40(4):841–845

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Witkin JM (1993) Blockade of the locomotor stimulant effects of cocaine and methamphetamine by glutamate antagonists. Life Sci 53(24):PL405-410

    Article  Google Scholar 

  38. 38.

    Somkuwar SS, Jordan CJ, Kantak KM, Dwoskin LP (2013) Adolescent atomoxetine treatment in a rodent model of ADHD: effects on cocaine self-administration and dopamine transporters in frontostriatal regions. Neuropsychopharmacology 38(13):2588–2597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lin HC, Wang SJ, Luo MZ, Gean PW (2000) Activation of group II metabotropic glutamate receptors induces long-term depression of synaptic transmission in the rat amygdala. J Neurosci 20(24):9017–9024

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Johnson KA, Niswender CM, Conn PJ, Xiang Z (2011) Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata. Neurosci Lett 504(2):102–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tang ZQ, Liu YW, Shi W, Dinh EH, Hamlet WR, Curry RJ, Lu Y (2013) Activation of synaptic group II metabotropic glutamate receptors induces long-term depression at GABAergic synapses in CNS neurons. J Neurosci 33(40):15964–15977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4(2):131–144

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E (2012) New perspectives in glutamate and anxiety. Pharmacol Biochem Behav 100(4):752–774

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Hashimoto K, Malchow B, Falkai P, Schmitt A (2013) Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263(5):367–377

    Article  PubMed  Google Scholar 

  45. 45.

    Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, Pilc A (2013) mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 66:40–52

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229(3):539–554

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Li X, Xi ZX, Markou A (2013) Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence. Neuropharmacology 66:12–23

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Counotte DS, Goriounova NA, Li KW, Loos M, van der Schors RC, Schetters D, Schoffelmeer AN, Smit AB, Mansvelder HD, Pattij T, Spijker S (2011) Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nat Neurosci 14(4):417–419

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Hascup ER, Hascup KN, Pomerleau F, Huettl P, Hajos-Korcsok E, Kehr J, Gerhardt GA (2012) An allosteric modulator of metabotropic glutamate receptors (mGluR(2)), (+)-TFMPIP, inhibits restraint stress-induced phasic glutamate release in rat prefrontal cortex. J Neurochem 122(3):619–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Koltunowska D, Gibula-Bruzda E, Kotlinska JH (2013) The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats. Prog Neuropsychopharmacol Biol Psychiatry 45:242–249

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Wang MJ, Li YC, Snyder MA, Wang H, Li F, Gao WJ (2013) Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons. PLoS ONE 8(4):e61787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68(5):2032–2037

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Gerasimov MR, Franceschi M, Volkow ND, Gifford A, Gatley SJ, Marsteller D, Molina PE, Dewey SL (2000) Comparison between intraperitoneal and oral methylphenidate administration: a microdialysis and locomotor activity study. J Pharmacol Exp Ther 295(1):51–57

    CAS  PubMed  Google Scholar 

  54. 54.

    Gerasimov MR, Franceschi M, Volkow ND, Rice O, Schiffer WK, Dewey SL (2000) Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse 38(4):432–437

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franceschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21(2):RC121

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Huff JK, Davies MI (2002) Microdialysis monitoring of methylphenidate in blood and brain correlated with changes in dopamine and rat activity. J Pharm Biomed Anal 29(5):767–777

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Marsteller DA, Gerasimov MR, Schiffer WK, Geiger JM, Barnett CR, Schaich Borg J, Scott S, Ceccarelli J, Volkow ND, Molina PE, Alexoff DL, Dewey SL (2002) Acute handling stress modulates methylphenidate-induced catecholamine overflow in the medial prefrontal cortex. Neuropsychopharmacology 27(2):163–170

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS (1996) Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci 58(12):231–239

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Rebec GV (2006) Behavioral electrophysiology of psychostimulants. Neuropsychopharmacology 31(11):2341–2348

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Kotecha SA, Oak JN, Jackson MF, Perez Y, Orser BA, Van Tol HH, MacDonald JF (2002) A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35(6):1111–1122

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Yuen EY, Liu W, Kafri T, van Praag H, Yan Z (2010) Regulation of AMPA receptor channels and synaptic plasticity by cofilin phosphatase Slingshot in cortical neurons. J Physiol 588(Pt 13):2361–2371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wultz B, Sagvolden T, Moser EI, Moser MB (1990) The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Neural Biol 53(1):88–102

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, Sagvolden G (1992) The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants. Behav Neural Biol 58(2):103–112

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    van den Bergh FS, Bloemarts E, Chan JS, Groenink L, Olivier B, Oosting RS (2006) Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder. Pharmacol Biochem Behav 83(3):380–390

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Barron E, Yang PB, Swann AC, Dafny N (2009) Adolescent and adult male spontaneous hyperactive rats (SHR) respond differently to acute and chronic methylphenidate (Ritalin). Int J Neurosci 119(1):40–58

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Crawford CA, McDougall SA, Meier TL, Collins RL, Watson JB (1998) Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum. Psychopharmacology 136(1):34–43

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Gaytan O, al-Rahim S, Swann A, Dafny N (1997) Sensitization to locomotor effects of methylphenidate in the rat. Life Sci 61(8):PL101–PL107

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    McDougall SA, Collins RL, Karper PE, Watson JB, Crawford CA (1999) Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing. Exp Clin Psychopharmacol 7(3):208–218

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Suzuki T, Shindo K, Miyatake M, Kurokawa K, Higashiyama K, Suzuki M, Narita M (2007) Lack of development of behavioral sensitization to methylphenidate in mice: correlation with reversible astrocytic activation. Eur J Pharmacol 574(1):39–48

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Wassum KM, Tolosa VM, Tseng TC, Balleine BW, Monbouquette HG, Maidment NT (2012) Transient extracellular glutamate events in the basolateral amygdala track reward-seeking actions. J Neurosci 32(8):2734–2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Shepard GM (2003) The synaptic organization of the brain, 3rd edn. Oxford University Press, New York

    Google Scholar 

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Correspondence to Greg A. Gerhardt.

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Miller, E.M., Quintero, J.E., Pomerleau, F. et al. Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD. Neurochem Res 44, 89–101 (2019). https://doi.org/10.1007/s11064-018-2483-1

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Keywords

  • ADHD
  • Spontaneously hypertensive rat
  • Tonic glutamate
  • Phasic glutamate
  • Pre-limbic cortex