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 SilvaEmail author
  • S. Nikolaus
  • A. Scorziello
  • M. Nieddu
  • G. Boatto
  • P. Illiano
  • C. Pagano
  • A. Tino
  • A. G. Sadile
Original Article


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.


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



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.


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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
    Email author
  • 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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