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Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors

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Abstract

Rationale

Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. Currently available ADHD drugs include the psychostimulants methylphenidate (MPH) and d-amphetamine (D-AMP), acting on norepinephrine and dopamine transporters/release, and atomoxetine (ATX), a selective norepinephrine uptake inhibitor. Recent evidence suggests an involvement of glutamate neurotransmission in the pathology and treatment of ADHD, via mechanisms to be clarified.

Objective

We have investigated how ADHD drugs could modulate, through interaction with catecholamine receptors, basal and glutamate-induced excitability of pyramidal neurons in the prefrontal cortex (PFC), a region which plays a major role in control of attention and impulsivity.

Methods

We have used the technique of extracellular single-unit recording in anaesthetised rats coupled with microiontophoresis.

Results

Both MPH (1–3 mg/kg) and d-AMP (1–9 mg/kg) increased the firing activity of PFC neurons in a dopamine D1 receptor-dependent manner. ATX administration (1–6 mg/kg) also increased the firing of neurons, but this effect is not significantly reversed by D1 (SCH 23390) or alpha1 (prazosin) receptor antagonists but potentiated by alpha2 antagonist (yohimbine). All drugs induced a clear potentiation of the excitatory response of PFC neurons to the microiontophoretic application of the glutamate agonist N-methyl-d-aspartate (NMDA), but not to the glutamate agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). The potentiating effect of d-AMP on NMDA-induced activation of PFC neurons was partially reversed or prevented by dopamine D1 receptor blockade.

Conclusion

Our data shows that increase in excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs.

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Abbreviations

ATX:

Atomoxetine

D-AMP:

d-Amphetamine

DAT:

Dopamine transporter

MPH:

Methylphenidate

NET:

Norepinephrine transporter

NMDA:

N-Methyl-d-aspartate

PFC:

Prefrontal cortex

References

  • Amitai N, Markou A (2010) Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol Psychiatry 68:5–16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bado P, Madeira C, Vargas-Lopes C, Moulin TC, Wasilewska-Sampaio AP, Maretti L, de Oliveira RV, Amaral OB, Panizzutti R (2011) Effects of low-dose D-serine on recognition and working memory in mice. Psychopharmacology (Berl) 218:461–470

    Article  CAS  Google Scholar 

  • Bartho P, Hirase H, Monconduit L, Zugaro M, Harris KD, Buzsaki G (2004) Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol 92:600–608

    Article  PubMed  Google Scholar 

  • Bristow LJ, Thorn L, Tricklebank MD, Hutson PH (1994) Competitive NMDA receptor antagonists attenuate the behavioural and neurochemical effects of amphetamine in mice. Eur J Pharmacol 264:353–359

    Article  CAS  PubMed  Google Scholar 

  • Bushe CJ, Savill NC (2014) Systematic review of atomoxetine data in childhood and adolescent attention-deficit hyperactivity disorder 2009–2011: focus on clinical efficacy and safety. J Psychopharmacol 28:204–211

    Article  PubMed  Google Scholar 

  • Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (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

    Article  CAS  PubMed  Google Scholar 

  • Carli M, Invernizzi RW (2014) Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task. Front Neural Circ 8:58

    Google Scholar 

  • Chang JP, Lane HY, Tsai GE (2014) Attention deficit hyperactivity disorder and N-methyl-D-aspartate (NMDA) dysregulation. Curr Pharm Des 20(32):5180–5185

  • Cheng J, Xiong Z, Duffney LJ, Wei J, Liu A, Liu S, Chen GJ, Yan Z (2014) Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors. Biol Psychiatry 76(12):953–962. doi:10.1016/j.biopsych.2014.04.003

  • Chue P (2013) Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: focus on the glycine transporter 1 (GlyT1). Curr Pharm Des 19:1311–1320

    CAS  PubMed  Google Scholar 

  • Cubillo A, Halari R, Smith A, Taylor E, Rubia K (2012) A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex 48:194–215

    Article  PubMed  Google Scholar 

  • Devilbiss DM, Berridge CW (2008) Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry 64:626–635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Devoto P, Flore G (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol 4:115–125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ding X, Qiao Y, Piao C, Zheng X, Liu Z, Liang J (2014) N-methyl-D-aspartate receptor-mediated glutamate transmission in nucleus accumbens plays a more important role than that in dorsal striatum in cognitive flexibility. Front Behav Neurosci 8:304

    Article  PubMed Central  PubMed  Google Scholar 

  • Dorval KM, Wigg KG, Crosbie J, Tannock R, Kennedy JL, Ickowicz A, Pathare T, Malone M, Schachar R, Barr CL (2007) Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder. Genes Brain Behav 6:444–452

    Article  CAS  PubMed  Google Scholar 

  • Easton N, Steward C, Marshall F, Fone K, Marsden C (2007) Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology 52:405–414

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Jaen A, Lopez-Martin S, Albert J, Fernandez-Mayoralas DM, Fernandez-Perrone AL, Tapia DQ, Calleja-Perez B (2014) Cortical thinning of temporal pole and orbitofrontal cortex in medication-naive children and adolescents with ADHD. Psychiatry Res 224(1):8–13. doi:10.1016/j.pscychresns.2014.07.004

  • Floresco SB (2013) Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions. Front Neurosci 7:62

    Article  PubMed Central  PubMed  Google Scholar 

  • Gamo NJ, Wang M, Arnsten AF (2010) Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry 49:1011–1023

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 51:485–492

    Article  CAS  PubMed  Google Scholar 

  • Gobbi G, Janiri L (2006) Sodium- and magnesium-valproate in vivo modulate glutamatergic and GABAergic synapses in the medial prefrontal cortex. Psychopharmacology (Berl) 185:255–262

    Article  CAS  Google Scholar 

  • Goldman-Rakic PS, Muly EC 3rd, Williams GV (2000) D (1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev 31:295–301

    Article  CAS  PubMed  Google Scholar 

  • Gronier B (2011) In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors. Eur Neuropsychopharmacol 21:192–204

    Article  CAS  PubMed  Google Scholar 

  • Gronier B, Aston J, Liauzun C, Zetterstrom T (2009) Age-dependent effects of methylphenidate in the prefrontal cortex: evidence from electrophysiological and Arc gene expression measurements. J Psychopharmacol 24:1819–1827

    Google Scholar 

  • Gronier B, Waters S, Ponten H (2013) The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex. J Neural Transm 120:1281–1294

    Article  CAS  PubMed  Google Scholar 

  • Gui ZH, Zhang QJ, Liu J, Zhang L, Ali U, Hou C, Fan LL, Sun YN, Wu ZH, Hui YP (2011) Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat. Neurochem Int 59:618–627

    Article  CAS  PubMed  Google Scholar 

  • Hajos M, Gartside SE, Varga V, Sharp T (2003) In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors. Neuropharmacology 45:72–81

    Article  CAS  PubMed  Google Scholar 

  • Heal DJ, Cheetham SC, Smith SL (2009) The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 57:608–618

    Article  CAS  PubMed  Google Scholar 

  • Hemrick-Luecke SK, Henderson MG, Fuller RW (1992) MK801 antagonism of the prolonged depletion of striatal dopamine by amphetamine in iprindole-treated rats. Life Sci 50:PL31–PL33

    CAS  PubMed  Google Scholar 

  • Hu JL, Liu G, Li YC, Gao WJ, Huang YQ (2010) Dopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons. Mol Brain 3:20

    Article  PubMed Central  PubMed  Google Scholar 

  • Kargieman L, Santana N, Mengod G, Celada P, Artigas F (2007) Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc Natl Acad Sci U S A 104:14843–14848

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kieling C, Goncalves RR, Tannock R, Castellanos FX (2008) Neurobiology of attention deficit hyperactivity disorder. Child and adolescent psychiatric clinics of North America 17:285–307

    Article  PubMed  Google Scholar 

  • Koda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T (2010) Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice. J Neurochem 114:259–270

    CAS  PubMed  Google Scholar 

  • Kritzer MF, Goldman-Rakic PS (1995) Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey. J Comp Neurol 359:131–143

    Article  CAS  PubMed  Google Scholar 

  • Kruse MS, Premont J, Krebs MO, Jay TM (2009) Interaction of dopamine D1 with NMDA NR1 receptors in rat prefrontal cortex. Eur Neuropsychopharmacol 19:296–304

    Article  CAS  PubMed  Google Scholar 

  • Kuriyama K, Honma M, Shimazaki M, Horie M, Yoshiike T, Koyama S, Kim Y (2011) An N-methyl-D-aspartate receptor agonist facilitates sleep-independent synaptic plasticity associated with working memory capacity enhancement. Sci Rep 1:127

    Article  PubMed Central  PubMed  Google Scholar 

  • Liston C, Malter Cohen M, Teslovich T, Levenson D, Casey BJ (2011) Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point? Biol Psychiatry 69:1168–1177

    Article  PubMed  Google Scholar 

  • Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Fohr KJ (2010) Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol 160:283–291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McLaughlin KA, Sheridan MA, Winter W, Fox NA, Zeanah CH, Nelson CA (2013) Widespread reductions in cortical thickness following severe early-life deprivation: a neurodevelopmental pathway to attention-deficit/hyperactivity disorder. Biol Psychiatry 76(8):629–638. doi:10.1016/j.biopsych.2013.08.016

  • Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603

    Article  CAS  PubMed  Google Scholar 

  • Nikiforuk A, Kos T, Rafa D, Behl B, Bespalov A, Popik P (2011) Blockade of glycine transporter 1 by SSR-504734 promotes cognitive flexibility in glycine/NMDA receptor-dependent manner. Neuropharmacology 61:262–267

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, San Diego

  • 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 164:942–948

    Article  PubMed  Google Scholar 

  • Povysheva NV, Zaitsev AV, Rotaru DC, Gonzalez-Burgos G, Lewis DA, Krimer LS (2008) Parvalbumin-positive basket interneurons in monkey and rat prefrontal cortex. J Neurophysiol 100:2348–2360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. Cereb Cortex 15:1–14

    Article  PubMed  Google Scholar 

  • Sarantis K, Matsokis N, Angelatou F (2009) Synergistic interactions of dopamine D1 and glutamate NMDA receptors in rat hippocampus and prefrontal cortex: involvement of ERK1/2 signaling. Neuroscience 163:1135–1145

    Article  CAS  PubMed  Google Scholar 

  • Schoemaker JH, Jansen WT, Schipper J, Szegedi A (2014) The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial. J Clin Psychopharmacol 34:190–198

    Article  CAS  PubMed  Google Scholar 

  • Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58

    Article  CAS  PubMed  Google Scholar 

  • Shen F, Tsuruda PR, Smith JA, Obedencio GP, Martin WJ (2013) Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model. PLoS One 8:e74891

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spiller HA, Hays HL, Aleguas A Jr (2013) Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management. CNS Drugs 27:531–543

    Article  CAS  PubMed  Google Scholar 

  • Sullivan RM, Brake WG (2003) What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function. Behav Brain Res 146:43–55

    Article  PubMed  Google Scholar 

  • Sun X, Zhao Y, Wolf ME (2005) Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. J Neurosci 25:7342–7351

    Article  CAS  PubMed  Google Scholar 

  • Swanson JM, Volkow ND (2003) Serum and brain concentrations of methylphenidate: implications for use and abuse. Neurosci Biobehav Rev 27:615–621

    Article  CAS  PubMed  Google Scholar 

  • Tierney PL, Thierry AM, Glowinski J, Deniau JM, Gioanni Y (2008) Dopamine modulates temporal dynamics of feedforward inhibition in rat prefrontal cortex in vivo. Cereb Cortex 18:2251–2262

    Article  CAS  PubMed  Google Scholar 

  • Trepanier CH, Jackson MF, MacDonald JF (2012) Regulation of NMDA receptors by the tyrosine kinase Fyn. FEBS J 279:12–19

    Article  CAS  PubMed  Google Scholar 

  • Tseng KY, O’Donnell P (2004) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 24:5131–5139

    Article  CAS  PubMed  Google Scholar 

  • Tseng KY, O’Donnell P (2007) Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex 17:1235–1240

    Article  PubMed Central  PubMed  Google Scholar 

  • Tseng KY, Mallet N, Toreson KL, Le Moine C, Gonon F, O’Donnell P (2006) Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo. Synapse 59:412–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Turic D, Langley K, Mills S, Stephens M, Lawson D, Govan C, Williams N, Van Den Bree M, Craddock N, Kent L, Owen M, O’Donovan M, Thapar A (2004) Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatry 9:169–173

    Article  CAS  PubMed  Google Scholar 

  • Upadhyaya HP, Desaiah D, Schuh KJ, Bymaster FP, Kallman MJ, Clarke DO, Durell TM, Trzepacz PT, Calligaro DO, Nisenbaum ES, Emmerson PJ, Schuh LM, Bickel WK, Allen AJ (2013) A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 226:189–200

    Article  CAS  Google Scholar 

  • Urban KR, Gao WJ (2013) Methylphenidate and the juvenile brain: enhancement of attention at the expense of cortical plasticity? Med Hypotheses 81:988–994

    Article  CAS  PubMed  Google Scholar 

  • Urban KR, Li YC, Gao WJ (2013) Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex. Neurobiol Learn Mem 101:65–74

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, O’Donnell P (2001) D (1) dopamine receptors potentiate nmda-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb Cortex 11:452–462

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu J, Gui ZH, Ali U, Fan LL, Hou C, Wang T, Chen L, Li Q (2011) alpha2-Adrenoceptor regulates the spontaneous and the GABA/glutamate modulated firing activity of the rat medial prefrontal cortex pyramidal neurons. Neuroscience 182:193–202

    Article  CAS  PubMed  Google Scholar 

  • Wood J, Kim Y, Moghaddam B (2012) Disruption of prefrontal cortex large scale neuronal activity by different classes of psychotomimetic drugs. J Neurosci 32:3022–3031

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yang CR, Chen L (2005) Targeting prefrontal cortical dopamine D1 and N-methyl-D-aspartate receptor interactions in schizophrenia treatment. Neuroscientist 11:452–470

    Article  CAS  PubMed  Google Scholar 

  • Yang P, Swann A, Dafny N (2000) NMDA receptor antagonist disrupts acute and chronic effects of methylphenidate. Physiol Behav 71:133–145

    Article  CAS  PubMed  Google Scholar 

  • Yeh GC, Chen JC, Tsai HC, Wu HH, Lin CY, Hsu PC, Peng YC (2002) Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated responses by directly interacting with the receptor/channel complex. J Pharmacol Exp Ther 300:1008–1016

    Article  CAS  PubMed  Google Scholar 

  • Zhang CL, Feng ZJ, Liu Y, Ji XH, Peng JY, Zhang XH, Zhen XC, Li BM (2012) Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action. PLoS One 7:e51910

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by internal DMU funds. The authors thank Mrs Anita O’Donoghue for excellent technical support and Dr. Florence Serres (Oxford University) for carefully reading the manuscript.

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Authors report no conflicts of interest.

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  1. Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK

    Mathieu Di Miceli & Benjamin Gronier

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  1. Mathieu Di Miceli
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Correspondence to Benjamin Gronier.

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Di Miceli, M., Gronier, B. Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors. Psychopharmacology 232, 2191–2205 (2015). https://doi.org/10.1007/s00213-014-3849-y

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