Functional Imaging Probes to Study the Neural Bases of Behavior in Genetic Animal Models of ADHD

A Comparative Analysis of Short and Long-Term Markers of Neuronal Activity
  • Michele Papa
  • Adolfo G. Sadile
  • Joseph A. Sergeant
  • Jason Shumake
  • F. Gonzalez-Lima


The following studies used molecular imaging techniques to trace the neural substrates of behavior in two genetic models of hyperactivity in rats. Additionally, the studies compared differences between markers sensitive to short-term changes and markers sensitive to longterm changes in neuronal activity. The first series of experiments used adult male Spontaneously Hypertensive Rats (SHR) with Wistar-Kyoto Normotensive (WKY) rats as controls. The second series used Naples-High Excitability (NHE) rats and Naples Low-Excitability (NLE) rats with random-bred (NRB) rats as controls. The following techniques were used to analyze the brains of these animals: (i) quantitative autoradiography of dopamine receptors, (ii) Ca2+/calmodulin-dependent protein kinase II (CaMKII) immunohistochemistry, (iii) transcription factors such as c-FOS, and (iv) quantitative cytochrome oxidase (C.O.) histochemistry. In Series 1 experiments, light microscope and computer assisted image analysis showed that the SHR had a higher density of binding sites for D-1/D-5 dopamine receptors and a reduced expression of CaMKII and c-FOS, but not JUN-B, in the most rostral portions of the caudate-putamen, the nucleus accumbens, and the olfactory tubercle. SHR also had a lower C.O. activity in the medial and lateral prefrontal cortices, compared to WKY controls. Furthermore, regional correlative analyses among different areas with different markers revealed that under basal conditions, SHR had reduced interregional correlations. In Series 2 experiments, C.O. metabolic differences between the NLE and NHE were found in the granular cell layer of the outer blade of the dentate gyrus. In addition, NLE showed greater C.O. activity than NRB in medial frontal cortex, and lower activity in perirhinal cortex (dorsal region). NHE showed greater C.O. activity than NRB in entorhinal cortex (superficial layers) and lower activities in perirhinal cortex and cortical amygdala. These data support the hypothesis that NLE/NHE rats may be an appropriate model for studying genetically altered limbic regions related to impaired emotional processing. Altogether, the results support the involvement of limbic cortico-striatal circuits in the anterior basal forebrain in attentive processes and impulsiveness, and support the use of the SHR and NHE strains as animal models of attention deficit hyperactivity disorder (ADHD) in children.


Attention Deficit Hyperactivity Disorder Attention Deficit Hyperactivity Disorder Child Medial Frontal Cortex Perirhinal Cortex Cytochrome Oxidase Activity 
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Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Michele Papa
    • 1
  • Adolfo G. Sadile
    • 1
  • Joseph A. Sergeant
    • 2
  • Jason Shumake
    • 3
  • F. Gonzalez-Lima
    • 3
  1. 1.Institute of Human Anatomy Laboratory Neurophysiology of Behaviour and Neural Networks Department of Human Physiology “F. Bottazzi”Second University of Naples (SUN)NaplesItaly
  2. 2.Department of Clinical PsychologyUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Institute for Neuroscience and Department of PsychologyUniversity of Texas at AustinAustinUSA

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