Neonatal hypothyroidism induces striatal dopaminergic dysfunction.
Oral administration of the antithyroid drug methimazole (50 mg/kg per day) to rats during the last six days of pregnancy, and subsequent daily s.c. injection of methimazole (20-30 mg/kg) to their pups from birth to postnatal day 30 provoked hormonal and somatic alterations resembling (with all caution to any association between rodent and human data) those of congenital hypothyroidism. The steady-state concentrations of striatal dopamine were similar in hypothyroid and euthyroid, 32-day-old rats, while the levels of the dopamine metabolites 3,4-dihydroxyphenylacetic and homovanillic acids were markedly decreased in hypothyroidism. The results of this and our earlier study [Vaccari A. and Gessa G. L. (1989) Neurochem. Res. 14, 949-955] show that the maximal synaptosomal uptake of [3H]dopamine, an index for the density of nigrostriatal dopaminergic terminals, and the maximum number of membrane [3H]tyramine binding sites, reflecting the concentration of the vesicular transporter for dopamine, were decreased in the hypothyroid striatum. There was also a loss of those D1-type dopaminergic receptors claimed to be located on neurons intrinsic to the striatum, and, consequently, dopamine-stimulated, D1-regulated adenylate cyclase activity was depressed. It is suggested that individual dopaminergic nerve endings in the neonatal hypothyroid striatum must contain more dopamine, owing to some loss of pertinent innervation and, therefore, to the presence of less vesicular transport sites for dopamine. Hypothyroidism-related decreases in the maximum number of striatal D1- and, reportedly, D2-receptors, plus the impairment of D1-coupled second messenger activity, may play a role in the derangement of those neurobehavioural patterns where a dopaminergic regulation is putatively implied.
Department of Neuroscience, Cagliari, Italy.
A
A
Vaccari
Z L
ZL
Rossetti
G
G
de Montis
E
E
Stefanini
E
E
Martino
G L
GL
Gessa
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001552:Benzazepines / Q000378:metabolism; D001835:Body Weight; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008713:Methimazole; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D012016:Reference Values; D013574:Synaptosomes / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D014439:Tyramine / Q000378:metabolism
D001552:Benzazepines; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D014284:Triiodothyronine; D015102:3,4-Dihydroxyphenylacetic Acid; D008713:Methimazole; D013974:Thyroxine; D004298:Dopamine; D006719:Homovanillic Acid; D014439:Tyramine