Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with onset at preschool age Approximately 5-10% of school-aged children worldwide have ADHD. Psychostimulants are the most common treatments for ADHD, although the precise etiology and pathological mechanisms underlying ADHD are poorly understood. Animal models could help to elucidate and further the understanding of this disorder. Among the major rodent models of ADHD of the genetic and neurotoxin-exposed animal models, the spontaneously hypertensive rats (SHR) are more extensively studied. Nevertheless, the mechanism of ADHD is complex and the evidence of SHR model for ADHD has been conflicting. Objective. In this work, we combined behavioral, neurochemical, neuroimaging, pharmacological and molecular studies to examine SHR as an animal model of ADHD. At the same time, the results of our studies could help us to explore the potential mechanism of ADHD. Material and methods. We compared the locomotor activity, attention, inhibition, learning and memory of juvenile male SHR with those of age- and gender-matched genetic control Wistar-Kyoto rats (WKY) by using the open field test, Morris water maze and prepulse inhibition test. We employed magnetic resonance imaging (MRI) to measure potential morphological differences between different brain areas of SHR and WKY, and the functional MRI (fMRI) for functional differences in these brain areas. We also measured dopamine concentration and dopamine related genes expression in the different dopamine pathways by using enzyme-linked immunosorbent assay (ELISA) to measure the dopamine concentration and by using real time PCR to assay genes expression. We examined SHR responses to D-amphetamine (D-AMP), which is psychostimulant. These included locomotor activity and inhibition ability during D-AMP treatment, expression of dopamine related genes after D-AMP treatment measured by real time PCR and c-fos protein after repeated treatment of D-AMP by the Western Blotting. Results . Hyperactivity, impulsivity and attention deficit were observed in SHR. Decreased brain volume in caudate-putamen and vermis cerebelli in SHR were demarcated using MRI. Functional MRI (fMRI) and altered c-fos expression indicated plasticity changes of the prefrontal cortex (PFC) in SHR. Dopamine content was found to decrease in mesocortical and mesolimbic dopamine pathways, but increased in the striatum. Dopamine D4 receptors gene and protein expression were decreased in the PFC in SHR. We also found that the expression of the synaptosomal-associated protein 25 (SNAP-25) gene was initially lower in the PFC but higher in the striatum in SHR. However, this disparity of SNAP-25 in the PFC vanished after repeated treatment of D-AMP between SHR and WKY. Conclusions. In the present study, we demonstrated that SHR could be established as an ADHD model by completing complex assessments of face validity, construct validity and prediction validity. We suggested that the "synaptogenesis hypotheses" might contribute to the abnormal release of dopamine and dysfunction of PFC and the striatum in SEER. In conclusion, our results have provided further new information relevant to the understanding of ADHD in human via the analysis of the SHR model. / Li, Qi. / Adviser: David Yen. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 1375. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 108-125). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344439 |
| Date | January 2007 |
| Contributors | Li, Qi, Chinese University of Hong Kong Graduate School. Division of Anatomy. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xii, 125 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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