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Amino Acids

, Volume 46, Issue 9, pp 2105–2122 | Cite as

Prepuberal intranasal dopamine treatment in an animal model of ADHD ameliorates deficient spatial attention, working memory, amino acid transmitters and synaptic markers in prefrontal cortex, ventral and dorsal striatum

  • L. A. Ruocco
  • C. Treno
  • U. A. Gironi Carnevale
  • C. Arra
  • C. Mattern
  • J. P. Huston
  • M. A. de Souza Silva
  • S. Nikolaus
  • A. Scorziello
  • M. Nieddu
  • G. Boatto
  • P. Illiano
  • C. Pagano
  • A. Tino
  • A. G. Sadile
Original Article

Abstract

Intranasal application of dopamine (IN-DA) has been shown to increase motor activity and to release DA in the ventral (VS) and dorsal striatum (DS) of rats. The aim of the present study was to assess the effects of IN-DA treatment on parameters of DA and excitatory amino acid (EAA) function in prepuberal rats of the Naples high-excitability (NHE) line, an animal model for attention-deficit hyperactivity disorder (ADHD) and normal random bred (NRB) controls. NHE and NRB rats were daily administered IN-DA (0.075, 0.15, 0.30 mg/kg) or vehicle for 15 days from postnatal days 28–42 and subsequently tested in the Làt maze and in the Eight-arm radial Olton maze. Soluble and membrane-trapped l-glutamate (l-Glu) and l-aspartate (l-Asp) levels as well as NMDAR1 subunit protein levels were determined after sacrifice in IN-DA- and vehicle-treated NHE and NRB rats in prefrontal cortex (PFc), DS and VS. Moreover, DA transporter (DAT) protein and tyrosine hydroxylase (TH) levels were assessed in PFc, DS, VS and mesencephalon (MES) and in ventral tegmental area (VTA) and substantia nigra, respectively. In NHE rats, IN-DA (0.30 mg/kg) decreased horizontal activity and increased nonselective attention relative to vehicle, whereas the lower dose (0.15 mg/kg) increased selective spatial attention. In NHE rats, basal levels of soluble EAAs were reduced in PFc and DS relative to NRB controls, while membrane-trapped EAAs were elevated in VS. Moreover, basal NMDAR1 subunit protein levels were increased in PFc, DS and VS relative to NRB controls. In addition, DAT protein levels were elevated in PFc and VS relative to NRB controls. IN-DA led to a number of changes of EAA, NMDAR1 subunit protein, TH and DAT protein levels in PFc, DS, VS, MES and VTA, in both NHE and NRB rats with significant differences between lines. Our findings indicate that the NHE rat model of ADHD may be characterized by (1) prefrontal and striatal DAT hyperfunction, indicative of DA hyperactivty, and (2) prefrontal and striatal NMDA receptor hyperfunction indicative of net EAA hyperactivty. IN-DA had ameliorative effects on activity level, attention, and working memory, which are likely to be associated with DA action at inhibitory D2 autoreceptors, leading to a reduction in striatal DA hyperactivity and, possibly, DA action on striatal EAA levels, resulting in a decrease of striatal EAA hyperfunction (with persistence of prefrontal EAA hyperfunction). Previous studies on IN-DA treatment in rodents have indicated antidepressant, anxiolytic and anti-parkinsonian effects in relation to enhanced central DAergic activity. Our present results strengthen the prospects of potential therapeutic applications of intranasal  DA by indicating an enhancement of selective attention and working memory in a deficit model.

Keywords

ADHD Intranasal dopamine l-Glutamate l-Aspartate NMDA receptor Dopamine transporter Tyrosine hydroxylase Working memory Attention 

Notes

Acknowledgments

This research was supported by the Young Investigator Project 2009-2012 from the Italian Ministry of Health to LAR (Principal Investigator WA). L.A. Ruocco, A. Tino and G.P. Boatto share equal first-authorship. We thank Dr. S. Anzilotti, Dept. Neuroscience, Univ. Naples Federico II, for micro photographs of brain slice preparations.

Conflict of interest

None of the authors declare any conflict of interest, except for C. Mattern, who is employed by M & P Pharma AG, Emmetten, Switzerland.

References

  1. Aspide R, Gironi Carnevale UA, Sergeant JA, Sadile AG (1998) Non-selective attention and nitric oxide in putative animal models of Attention-Deficit Hyperactivity Disorder. Behav Brain Res 95:123–133PubMedCrossRefGoogle Scholar
  2. Barbeito L, Girault JA, Godeheu G, Pittaluga A, Glowinski J, Cheramy A (1989) Activation of the bilateral corticostriatal glutamatergic projection by infusion of GABA into thalamic motor nuclei in the cat: an in vivo release study. Neuroscience 28:365–374PubMedCrossRefGoogle Scholar
  3. Berke JD, Breck JT, Eichenbaum H (2009) Striatal versus hippocampal representations during win-stay maze performance. J Neurophysiol 101:1575–1587PubMedCentralPubMedCrossRefGoogle Scholar
  4. Buddenberg TE, Topic B, Mahlberg ED, De Souza Silva MA, Huston JP, Mattern C (2008) Behavioral actions of intranasal application of dopamine: effects on forced swimming, elevated plus-maze and open field parameters. Neuropsychobiology 57:70–79PubMedCrossRefGoogle Scholar
  5. Capowski JJ (1989) Computer techniques in neuroanatomy. Plenum, New YorkCrossRefGoogle Scholar
  6. Chemuturi NV, Haraldsson JE, Prisinzano T, Donovan M (2006) Role of dopamine transporter (DAT) in dopamine transport across the nasal mucosa. Life Sci 79:1391–1398PubMedCrossRefGoogle Scholar
  7. Chen N, Reith ME (2000) Structure and function of the dopamine transporter. Eur J Pharmacol 405:329–339PubMedCrossRefGoogle Scholar
  8. Clow DW, Jhamandas K (1989) Characterization of l-glutamate action on the release of endogenous dopamine from the rat caudate-putamen. J Pharmacol Exp Ther 248:722–728PubMedGoogle Scholar
  9. Dahlin M, Bergman U, Jansson B, Bjork E, Brittebo E (2000) Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 17:737–742PubMedCrossRefGoogle Scholar
  10. Dahlin M, Jansson B, Bjork E (2001) Levels of dopamine in blood and brain following nasal administration to rats. Eur J Pharm Sci 14:75–80PubMedCrossRefGoogle Scholar
  11. D’Aniello A (2007) d-Aspartic acid: an endogenous amino acid with an important neuroendocrine role. Brain Res Rev 53:215–234PubMedCrossRefGoogle Scholar
  12. De Souza Silva MA, Topic B, Huston JP, Mattern C (2008) Intranasal dopamine application increases dopaminergic activity in the neostriatum and nucleus accumbens and enhances motor activity in the open field. Synapse 62:176–184PubMedCrossRefGoogle Scholar
  13. Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW (2011) The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry 69:e145–e157PubMedCrossRefGoogle Scholar
  14. 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 6:444–452PubMedCrossRefGoogle Scholar
  15. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ (1999) Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354:2132–2133PubMedCrossRefGoogle Scholar
  16. Dresel S, Krause J, Krause KH, LaFougere C, Brinkbäumer K, Kung HF, Hahn K, Tatsch K (2000) Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 27:1518–1524PubMedCrossRefGoogle Scholar
  17. Errico F, Rossi S, Napolitano F, Catuogno V, Topo E, Fisone G, D’Aniello A, Centonze D, Usiello A (2008) d-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci 28:10404–10414PubMedCrossRefGoogle Scholar
  18. Flint RS, Murphy JM, Calkins PM, McBride WJ (1985) Monoamine, amino acid and cholinergic interactions in slices of rat cerebral cortex. Brain Res Bull 15:197–202PubMedCrossRefGoogle Scholar
  19. Fumagalli F, Frasca A, Racagni G, Riva MA (2008) Dynamic regulation of glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs. Mol Pharmacol 73:1484–1490Google Scholar
  20. Graff CL, Pollack GM (2005) Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci 94:1187–1195PubMedCrossRefGoogle Scholar
  21. Hoerst M, Weber-Fahr W, Tunc-Skarka N, Ruf M, Bohus M, Schmahl C, Ende G (2010) Correlation of glutamate levels in the anterior cingulate cortex with self-reported impulsivity in patients with borderline personality disorder and healthy controls. Arch Gen Psychiatry 67:946–954PubMedCrossRefGoogle Scholar
  22. Hosenbocus S, Chahal R (2013a) Amantadine: a review of use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22:55–60PubMedCentralPubMedGoogle Scholar
  23. Hosenbocus S, Chahal R (2013b) Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22:166–171PubMedCentralPubMedGoogle Scholar
  24. Illum L (2007) Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J Pharm Sci 96:473–483PubMedCrossRefGoogle Scholar
  25. Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L (2005) Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatry 57:229–238PubMedCrossRefGoogle Scholar
  26. Krause J (2008) SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder. Expert Rev Neurother 8:611–625PubMedCrossRefGoogle Scholar
  27. Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K (2000) Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Neurosci Lett 285:107–110PubMedCrossRefGoogle Scholar
  28. La Fougere C, Krause J, Krause KH, Josef Gildehaus F, Hacker M, Koch W, Hahn K, Tatsch K, Dresel S (2006) Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder. Nucl Med Commun 27:733–737PubMedCrossRefGoogle Scholar
  29. Langer SZ (1997) 25 years since the discovery of presynaptic receptors: present knowledge and future perspectives. Trends Pharmacol Sci 18:95–99PubMedCrossRefGoogle Scholar
  30. Larisch R, Sitte W, Antke C, Nikolaus S, Franz M, Tress W, Müller HW (2006) Striatal dopamine transporter density in drug naive patients with attention-deficit/hyperactivity disorder. Nucl Med Commun 27:267–270PubMedCrossRefGoogle Scholar
  31. Lesch KP, Merker S, Reif A, Novak M (2013) Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD. Eur Neuropsychopharmacol 23:479–491PubMedCrossRefGoogle Scholar
  32. Nikolaus S, Antke C, Müller HW (2009) In vivo imaging of synaptic function in the central nervous system. II. Mental and affective disorders. Behav Brain Res 204:32–66PubMedCrossRefGoogle Scholar
  33. Nikolaus S, Beu M, Antke C, Müller HW (2010) Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders—results from in vivo imaging studies. Rev Neurosci 21:119–139PubMedCrossRefGoogle Scholar
  34. Nikolaus S, Hautzel H, Heinzel A, Müller HW (2012) Key players in major and bipolar depression—a retrospective analysis of in vivo imaging studies. Behav Brain Res 232:358–390PubMedCrossRefGoogle Scholar
  35. Nikolaus S, Hautzel H, Heinzel A, Müller HW (2014) Neurochemical dysfunction in treated and nontreated schizophrenia—a retrospective analysis of in vivo imaging studies. Rev Neurosci 25:25–96PubMedCrossRefGoogle Scholar
  36. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic Press, LondonGoogle Scholar
  37. Peris J, Dunwiddie TV (1985) Inhibitory neuromodulation of release of amino acid neurotransmitters. Alcohol Drug Res 6:253–264PubMedGoogle Scholar
  38. Pum ME, Schäble S, Harooni HE, Topic B, de Souza Silva MA, Li J-S, Mattern C, Huston JP (2009) Effects of intranasally applied dopamine on behavioral asymmetries in rats with unilateral 6-OHDA lesions of the nigro-striatal tract. Neuroscience 162(1):174–183PubMedCrossRefGoogle Scholar
  39. Purper-Ouakil D, Wohl M, Michel G, Mouren MC, Gorwood P (2004) Symptom variations in ADHD: importance of context, development and comorbidity. Encephale 30:533–539PubMedCrossRefGoogle Scholar
  40. Rodriguez FJ, Lluch M, Dot J, Blanco I, Rodriguez-Alvarez J (1997) Histamine modulation of glutamate release from hippocampal synaptosomes. Eur J Pharmacol 323:283–286PubMedCrossRefGoogle Scholar
  41. Ruocco LA, de Souza Silva MA, Topic B, Mattern C, Huston JP, Sadile AG (2009a) Intranasal application of dopamine reduces activity and improves attention in Naples High Excitability rats that feature the mesocortical variant of ADHD. Eur Neuropsychopharmacol 19:693–701PubMedCrossRefGoogle Scholar
  42. Ruocco LA, Gironi Carnevale UA, Sica A, Arra C, Topo E, Di MA, D’Aniello A, Sadile AG (2009b) Elevated forebrain excitatory l-glutamate, l-aspartate and d-aspartate in the Naples high-excitability rats. Behav Brain Res 198:24–28PubMedCrossRefGoogle Scholar
  43. Ruocco LA, Sadile AG, Gironi Carnevale UA (2009c) Modeling the mesocortical mariant of ADHD: the Naples high excitability rats. In: Gordon SM, Mitchell AM (eds) Attention deficit hyperactivity disorder. Nova Science, New York, pp 85–106Google Scholar
  44. Ruocco LA, Gironi Carnevale UA, Sica A, Arra C, Topo E, Di Maio A, Di Giovanni M, D’ Aniello A, Sadile AG (2009d) Differential prepuberal handling modifies behaviour and excitatory amino acids in the forebrain of the naples high-excitability rats. Behav Brain Res 198:29–36PubMedCrossRefGoogle Scholar
  45. Rüsch N, Boeker M, Büchert M, Glauche V, Bohrmann C, Ebert D, Lieb K, Hennig J, Tebartz Van Elst L (2010) Neurochemical alterations in women with borderline personality disorder and comorbid attention-deficit hyperactivity disorder. World J Biol Psychiatry 11:372–381PubMedCrossRefGoogle Scholar
  46. Russell VA (2011) Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci Chapter 9(Unit9):35Google Scholar
  47. Sadile AG, Gironi Carnevale UA, Vitullo E, Cioffi LA, Welzl H, Bättig K (1988) Maze learning of the Naples High- and Low-Excitability rat lines. Adv Biosci 70:177–180CrossRefGoogle Scholar
  48. Sadile AG, Pellicano MP, Sagvolden T, Sergeant JA (1996) NMDA and non-NMDA sensitive [L-3H]glutamate receptor binding in the brain of the Naples high- and low-excitability rats: an autoradiographic study. Behav Brain Res 78(2):163–174PubMedCrossRefGoogle Scholar
  49. 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 24:31–40PubMedCrossRefGoogle Scholar
  50. Sergeant JA, Geurts H, Huijbregts S, Scheres A, Oosterlaan J (2003) The top and the bottom of ADHD: a neuropsychological perspective. Neurosci Biobehav Rev 27:583–592PubMedCrossRefGoogle Scholar
  51. Solanto MV (1998) Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 94:127–152PubMedCrossRefGoogle Scholar
  52. Sonuga-Barke EJ (2003) The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev 27:593–604PubMedCrossRefGoogle Scholar
  53. Spencer TJ, Biederman J, Madras BK, Dougherty DD, Bonab AA, Livni E, Meltzer PC, Martin J, Rauch S, Fischman AJ (2007) Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane. Biol Psychiatry 62:1059–1061PubMedCentralPubMedCrossRefGoogle Scholar
  54. Steinhoff KW (2008) Special issues in the diagnosis and treatment of ADHD in adolescents. Postgrad Med 120:60–68PubMedCrossRefGoogle Scholar
  55. Tayebati SK, Nwankwo IE, Amenta F (2013) Intranasal drug delivery to the central nervous system: present status and future outlook. Curr Pharm Des 19:510–526PubMedCrossRefGoogle Scholar
  56. Thorne RG, Frey WH (2001) Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet 40:907–946PubMedCrossRefGoogle Scholar
  57. Tolleson C, Claassen D (2012) The function of tyrosine hydroxylase in the normal and Parkinsonian brain. CNS Neurol Disord Drug Targets 11:381–386PubMedCrossRefGoogle Scholar
  58. Van Dyck CH, Quinlan DM, Cretella LM, Staley JK, Malison RT, Baldwin RM, Seibyl JP, Innis RB (2002) Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 159:309–312PubMedCrossRefGoogle Scholar
  59. Viggianao D, Sadile AG (2000) Hypertrophic A10 dopamine neurones in a rat model of attention-deficit hyperactivity disorder (ADHD). Neuroreport 11:3677–3680CrossRefGoogle Scholar
  60. Viggiano D, Vallone D, Welzl H, Sadile AG (2002a) The Naples high- and low-excitability rats: selective breeding, behavioral profile, morphometry, and molecular biology of the mesocortical dopamine system. Behav Genet 32:315–333PubMedCrossRefGoogle Scholar
  61. Viggiano D, Grammatikopoulos G, Sadile AG (2002b) A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD. Behav Brain Res 130:181–189PubMedCrossRefGoogle Scholar
  62. Viggiano D, Vallone D, Ruocco LA, Sadile AG (2003) Behavioural, pharmacological, morpho-functional molecular studies reveal a hyperfunctioning mesocortical dopamine system in an animal model of attention deficit and hyperactivity disorder. Neurosci Biobehav Rev 27:683–689PubMedCrossRefGoogle Scholar
  63. Volkow ND, Wang GJ, Fowler JS, Ding YS (2005) Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit hyperactivity disorder. Biol Psychiatry 57:1410–1415PubMedCrossRefGoogle Scholar
  64. Yamamoto BK, Davy S (1992) Dopaminergic modulation of glutamate release in striatum as measured by microdialysis. J Neurochem 58:1736–1742PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • L. A. Ruocco
    • 1
  • C. Treno
    • 1
  • U. A. Gironi Carnevale
    • 1
  • C. Arra
    • 4
  • C. Mattern
    • 6
  • J. P. Huston
    • 2
  • M. A. de Souza Silva
    • 2
  • S. Nikolaus
    • 7
  • A. Scorziello
    • 8
  • M. Nieddu
    • 3
  • G. Boatto
    • 3
  • P. Illiano
    • 5
  • C. Pagano
    • 5
  • A. Tino
    • 5
  • A. G. Sadile
    • 1
  1. 1.Department of Exptl. Med., School of MedicineSecond University of NaplesNaplesItaly
  2. 2.Center for Behavioral Neuroscience, Institute of Experimental PsychologyUniversity of DüsseldorfDüsseldorfGermany
  3. 3.Department of Chemistry and PharmacySassari UniversitySassariItaly
  4. 4.Animal FacilityI.N.T.G. PascaleNaplesItaly
  5. 5.Istituto di Cibernetica “Eduardo Caianiello” ICIB CNRPozzuoliItaly
  6. 6.M et P Pharma AG, Emetten, Switzerland, and Oceanographic Center, Nova Southeastern UniversityFloridaUSA
  7. 7.Clinic of Nuclear MedicineUniversity Hospital DüsseldorfDüsseldorfGermany
  8. 8.Department of Neuroscience, Reproductive and Odontostomatological SciencesSecond University of NaplesNaplesItaly

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