Dopamine D(2)-like receptor function is converted from excitatory to inhibitory by thyroxine in the developmental hippocampus.

The mechanism by which a lack of thyroid hormone in the early development of the brain causes permanent mental retardation in cretins is currently unknown. On the other hand, an abnormality in dopamine-related brain function is believed to underlie some forms of mental illness. In this study, we demonstrate that although the activation of a dopaminergic D(2)-like receptor inhibited glutamatergic transmission in the hippocampal slices of normal adult rats, indicating the inhibitory action of the D(2)-like receptor on glutamatergic transmission, it markedly enhanced glutamatergic transmission both in a mutant hypothyroid rat with a missense mutation in thyroglobulin and in hypothyroid rats treated with methylmercaptoimidazole (MMI), indicating the excitatory action of the D(2)-like receptor on glutamatergic transmission. Paired pulse facilitation of field excitatory postsynaptic potentials was reduced by the activation of the D(2)-like receptors from MMI-induced hypothyroid rats, suggesting a presynaptic locus of the excitatory action of the D(2)-like receptors. In normal rats, the excitatory D(2)-like dopamine receptors were observed in the developing stages and were completely replaced by normal inhibitory responses up to adulthood. Furthermore, the continuous supplement of thyroxine from birth exerted a normalising effect on the abnormal excitatory property of D(2)-like dopamine receptors in the hippocampal slices of MMI-treated hypothyroid rats. From these results, it is suggested that thyroxine may play a crucial role in reversing the excitatory property of D(2)-like dopaminergic receptors in the immature brain to an inhibitory one in the mature brain. Moreover, we suggest that the abnormal excitatory property of D(2)-like dopaminergic receptors may develop in response to a lack of thyroxine and may contribute to some central nervous system deficits, including cognitive dysfunctions accompanied by hypothyroidism.