Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism

Thyroid hormone (TH) is essential for normal brain development. TH insufficiency during early stages of development may increase the risk for attention deficit/hyperactivity disorder, in which malfunction of brain monoaminergic systems is likely involved. However, little is known about the effects of perinatal hypothyroidism on behaviors and brain monoaminergic systems in offspring mice. The present study examined in mice (1) whether perinatal hypothyroidism causes hyperactive behavioral phenotypes, (2) how perinatal hypothyroidism influences brain monoaminergic systems, and (3) whether hyperactive behavioral phenotypes are associated with the state of brain monoaminergic systems. When dams were exposed to propylthiouracil, offspring mice developed hypothyroidism during the perinatal period. Offspring mice with perinatal hypothyroidism exhibited hyperactive behavioral phenotypes such as hyper-ambulatory activity and an increased response rate in the two-way active avoidance test in a male-specific manner. Significant decreases in dopamine (DA) and serotonin turnover were observed in the striatum (ST), nucleus accumbens, hypothalamus, and hippocampus in male mice with perinatal hypothyroidism. A significant correlation between ambulatory activity and DA turnover in the ST and an augmented ambulatory response to the DA reuptake inhibitor bupropion suggested that DA in the ST was involved in the hyper-ambulatory activity in mice with perinatal hypothyroidism.