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Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder

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Abstract

Rationale

The psychomotor stimulant methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD). Whereas the mechanism is not fully understood it is suggested to involve restoration of impaired dopamine function found in ADHD.

Objectives

The aim of this study was to determine the effects of methylphenidate on brain region activation in vivo using pharmacological magnetic resonance imaging (phMRI) in a potential rat model of ADHD.

Methods

Rats were treated bi-daily [from postnatal day (PND) 24] for 4 days with the dopamine re-uptake inhibitor GBR 12909 (30 mg/kg i.p) or vehicle (control). On PND 57 rats were administered methylphenidate (4 mg/kg i.p) and locomotor activity measured. In a separate group of animals, blood oxygen level dependent (BOLD) response was measured using phMRI to determine changes in brain region activation produced by methylphenidate (4 mg/kg i.p.) in GBR 12909-pretreated or control rats.

Results

Methylphenidate produced a greater locomotor-stimulant response in controls compared with GBR 12909 rats. Pretreatment with GBR 12909 reduced the BOLD response produced by methylphenidate compared with that in control animals. The main effects of methylphenidate on the BOLD response were seen in the caudate, frontal cortex, hippocampus and hypothalamus.

Conclusions

Short-term treatment with GBR 12909 in young rats causes long-term changes in dopaminergic systems, altering the methylphenidate-induced behavioural response and brain region activation compared with that in vehicle-pretreated rats. The results further support the view that altered dopaminergic function may be an important factor in ADHD and the value of animal models with this functional neurochemical deficit.

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References

  • Andersen PH (1989) The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol 166(3):493–504

    Article  CAS  PubMed  Google Scholar 

  • Anderson CM, Polcari A, Lowen SB, Renshaw PF, Teicher MH (2002) Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD. Am J Psychiatry 159(8):1322–1328

    Article  PubMed  Google Scholar 

  • Barkley AR (1998) Attention deficit hyperactivity disorder, 2nd edn. Guilford, New York

    Google Scholar 

  • Beninger RJ (1983) The role of dopamine in locomotor activity and learning. Brain Res 287(2):173–196

    CAS  PubMed  Google Scholar 

  • Bull E, Reavill C, Hagan JJ, Overend P, Jones DN (2000) Evaluation of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder: acquisition and performance of the DRL-60s test. Behav Brain Res 109(1):27–35

    Article  CAS  PubMed  Google Scholar 

  • Castellanos FX, Elia J, Kruesi MJ, Marsh WL, Gulotta CS, Potter WZ, Ritchie GF, Hamburger SD, Rapoport JL (1996) Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder. Neuropsychopharmacology 14(2):125–137

    Article  CAS  PubMed  Google Scholar 

  • Clemett DA, Cockett MI, Marsden CA, Fone KCFF (1998) Antisense oligonucleotide–induced reduction in 5-HT7 receptors in the rat hypothalamus without alteration in exploratory behaviour in neuroendocrine function. J Neurochem 71:1271–1279

    CAS  PubMed  Google Scholar 

  • Durston S (2003) A review of the biological bases of ADHD: what have we learned from imaging studies? Ment Retard Dev Disabil Res Rev 9(3):184–195

    Article  PubMed  Google Scholar 

  • Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ (1995) Human brain mapping 1:214-220 [SPM_3] statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapping 2:189–210

    Article  Google Scholar 

  • Gaytan O, Ghelani D, Martin S, Swann A, Dafny N (1996) Dose response characteristics of methylphenidate on different indices of rats’ locomotor activity at the beginning of the dark cycle. Brain Res 727(1–2):13–21

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Heikkila RE, Manzino L (1984) Behavioral properties of GBR 12909, GBR 13069 and GBR 13098: specific inhibitors of dopamine uptake. Eur J Pharmacol 103(3–4):241–248

    Article  CAS  PubMed  Google Scholar 

  • Hewitt KN, Harwood B, Winney C, Penkethman S, Hollis C, Marsden CA, Fone KCF (2001) Evaluation of a potential new animal model of attention deficit hyperactivity disorder. J Psychopharmacol 15:A68

    Google Scholar 

  • Hewitt KN, Prior MJW, Hollis C, Marsden CA, Morris PG, Fone KCF (2002) Alterations in regional cerebral blood flow (fMRI) induced by the dopamine transporter inhibitor GBR 12909 in the rat. J Psychopharmacol 16:A6

    Google Scholar 

  • Hewitt KN, Beal DJ, Hollis C, King MV, Marsden CA, Fone KCF (2004) GBR 12909 pre-treatment in rats alters attentional components of the 5-CSRTT during training and test sessions; A potential model for ADHD. J Psychopharmacol 18(3):A52

    Google Scholar 

  • Kim BN, Lee JS, Cho SC, Lee DS (2001) Methylphenidate increased regional cerebral blood flow in subjects with attention deficit/hyperactivity disorder. Yonsei Med J 42(1):19–29

    CAS  PubMed  Google Scholar 

  • Koelega HS (1993) Stimulant drugs and vigilance performance: a review. Psychopharmacology 111(1):1–16

    Article  CAS  PubMed  Google Scholar 

  • Krause KH, Dresel SH, Krause J, la Fougere C, Ackenheil M (2003) The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder. Neurosci Biobehav Rev 27(7):605–613

    Article  CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68(5):2032–2037. Erratum in J Neurochem 69(3):1332

    Article  CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (1999) Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate. Psychopharmacology 147(1):96–103

    Article  CAS  PubMed  Google Scholar 

  • Kunko PM, Loeloff RJ, Izenwasser S (1997) Chronic administration of the selective uptake inhibitor BGR 12909, but not cocaine, produces marked decreases in dopamine transporter density. Naunyn-Schmiedeberg’s Arch Pharmacol 356:562–569

    Article  CAS  Google Scholar 

  • Lipska BK, Jaskiw GE, Braun AR, Weinberger DR (1995) Prefrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Biol Psychiatry 38(4):255–262

    Article  CAS  PubMed  Google Scholar 

  • Lou HC, Henriksen L, Bruhn P (1984) Focal cerebral hypoperfusion in children with dysphasia and/or attention deficit disorder. Arch Neurol 41(8):825–829

    CAS  PubMed  Google Scholar 

  • Lu W, Wolf ME (1997) Expression of dopamine transporter and vesicular monoamine transporter 2 mRNAs in rat midbrain after repeated amphetamine administration. Brain Res Mol Brain Res 49(1–2):137–148

    Article  CAS  PubMed  Google Scholar 

  • Madras BK, Miller GM, Fischman AJ (2002) The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD). Behav Brain Res 130(1–2):57–63

    Article  CAS  PubMed  Google Scholar 

  • Marriott AS (1986) The effects of amphetamine, caffeine and methylphenidate on the locomotor activity of rats in an unfamiliar environment. Int J Neuropharmacol 7(6):487–491

    Article  Google Scholar 

  • Matochik JA, Nordahl TE, Gross M, Semple WE, King AC, Cohen RM, Zametkin AJ (1993) Effects of acute stimulant medication on cerebral metabolism in adults with hyperactivity. Neuropsychopharmacology 8(4):377–386

    CAS  PubMed  Google Scholar 

  • Matochik JA, Liebenauer LL, King AC, Szymanski HV, Cohen RM, Zametkin AJ (1994) Cerebral Glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry 151(5):658–664

    CAS  PubMed  Google Scholar 

  • Rao SM, Salmeron BJ, Durgerian S, Janowiak JA, Fischer M, Risinger RC, Conant LL, Stein EA (2000) Effects of methylphenidate on functional MRI blood-oxygen-level-dependent contrast. Am J Psychiatry 157(10):1697–1699

    Article  CAS  PubMed  Google Scholar 

  • Ross SB (1979) The central stimulatory action of inhibitors of the dopamine uptake. Life Sci 24(2):159–167

    Article  CAS  PubMed  Google Scholar 

  • Russell VA, de Villiers AS, Sagvolden T, Lamm MC, Taljaard JJ (2000) Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder—the spontaneously hypertensive rat. Brain Res Bull 53(2):187–192

    Article  CAS  PubMed  Google Scholar 

  • Sagvolden T (2000) Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci Biobehav Rev 24(1):31–39

    Article  CAS  PubMed  Google Scholar 

  • Sagvolden T, Sergeant JA (1998) Attention deficit/hyperactivity disorder—from brain dysfunctions to behaviour. Behav Brain Res 94(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Shah YB, Marsden CA (2004) The application of functional magnetic resonance imaging to neuropharmacology. Curr Opin Pharmacol 4(5):517–521

    Article  CAS  PubMed  Google Scholar 

  • Shah YB, Prior MJ, Dixon AL, Morris PG, Marsden CA (2004) Detection of cannabinoid agonist evoked increase in BOLD contrast in rats using functional magnetic resonance imaging. Neuropharmacology 46(3):379–387

    Article  CAS  PubMed  Google Scholar 

  • Sproson EJ, Chantrey J, Hollis C, Marsden CA, Fone KC (2001) Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats. J Psychopharmacol 15(2):67–75

    Article  CAS  PubMed  Google Scholar 

  • Steward CA, Marsden CA, Prior MJW, Morris PG, Shah YB (2005) Methodological considerations in rat brain BOLD contrast pharmacological MRI. Psychopharmacology (this issue)

  • Swanson JM, Flodman P, Kennedy J, Spence MA, Moyzis R, Schuck S, Murias M, Moriarity J, Barr C, Smith M, Posner M (2000) Dopamine genes and ADHD. Neurosci Biobehav 24(1):21–25

    Article  CAS  Google Scholar 

  • Teicher MH, Anderson CM, Polcari A, Glod CA, Maas LC, Renshaw PF (2000) Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. Nat Med 6(4):470–473

    Article  CAS  PubMed  Google Scholar 

  • Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH, Gabrieli JD (1998) Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci U S A 95(24):14494–14499

    Article  CAS  PubMed  Google Scholar 

  • van der Zee P, Koger HS, Gootjes J, Hespe W (1980) Aryl 1,4-dialk(en)ylpiperazines as selective and very potent inhibitors of dopamine uptake. Eur J Med Chem 15:363

    Google Scholar 

  • 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  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM (2004) Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 161(7):1173–1180

    Article  PubMed  Google Scholar 

  • 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 

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Acknowledgements

K.N.H. was funded by a PPP Healthcare Trust grant. Methylphenidate was donated by Novartis. The authors thank Magrit Mitchell for care of the animals and Carolyn Steward for tutorials on phMRI data processing.

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Authors and Affiliations

  1. Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    Katherine N. Hewitt

  2. Institute of Neuroscience, Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, Nottingham, UK

    Yasmene B. Shah, Malcolm J. W. Prior & Peter G. Morris

  3. Institute of Neuroscience, Developmental Psychiatry, Division of Psychiatry, Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    Chris P. Hollis

  4. Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    Kevin C. F. Fone & Charles A. Marsden

Authors
  1. Katherine N. Hewitt
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  2. Yasmene B. Shah
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  3. Malcolm J. W. Prior
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  4. Peter G. Morris
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  5. Chris P. Hollis
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  6. Kevin C. F. Fone
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  7. Charles A. Marsden
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Correspondence to Katherine N. Hewitt.

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Hewitt, K.N., Shah, Y.B., Prior, M.J.W. et al. Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder. Psychopharmacology 180, 716–723 (2005). https://doi.org/10.1007/s00213-005-2272-9

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  • DOI: https://doi.org/10.1007/s00213-005-2272-9

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