Journal
PSYCHONEUROENDOCRINOLOGY
Volume 48, Issue -, Pages 147-161Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.psyneuen.2014.05.021
Keywords
Thyrotropin receptor; Attention deficit/hyperactivity disorder; Methylphenidate; Monoamine; Noradrenaline transporter
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) [22248033, 20390073, 21390045, 26460240, 23791325, 26860175, 19659017, 22659213]
- Regional Joint Research Program
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Project for Researching the Regulation of Pharmaceuticals and Medical Devices (Ministry of Health and Labour and Welfare [MHLW])
- Japan-Korea Basic Scientific Cooperation Program (Japan Society for the Promotion of Science [JSPS])
- Smoking Research Foundation Grant for Biomedical
- Funding Program for Next Generation World Leading Researchers (NEXT Program)
- Council for Science and Technology Policy (CSTP) [LS055]
- Grants-in-Aid for Scientific Research [19659017, 26860175, 26000013, 23791325, 26860163] Funding Source: KAKEN
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Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor beta (TR beta) gene. TR beta is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10 mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD. (C) 2014 Elsevier Ltd. All rights reserved.
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