title: Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction.
abstract: 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 β (TRβ) gene. TRβ 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 10mg/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.
authors.affiliation: Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya 468-0069, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Laboratory of Animal Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hoshino
authors.affiliation: Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Narusawa
authors.affiliation: Laboratory of Animal Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ikegami
authors.affiliation: Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Laboratory of Animal Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan; Department of Regional Pharmaceutical Care and Sciences, Meijo University, Nagoya 468-8503, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya 468-0069, Japan. Electronic address: tnabeshi@ccalumni.meijo-u.ac.jp.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000342:Affective Symptoms / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D015306:Biogenic Monoamines / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics; D004644:Emotions / Q000187:drug effects; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D015306:Biogenic Monoamines; D011989:Receptors, Thyrotropin; D008774:Methylphenidate
keywords: Attention deficit/hyperactivity disorder; Methylphenidate; Monoamine; Noradrenaline transporter; Thyrotropin receptor