Effects of copper on dopaminergic function in the rat corpus striatum

Copper-loading was produced in rats by administration of 0.125% CuSO4 in the drinking water for a period of 11 months from weaning. At conclusion of the treatment the animals had significant increases in liver (552%) and brain (26%) copper content relative to age-matched controls. Whereas the concentration of dopamine was unaffected, the concentration of 3,4-dihydroxyphenylacetic acid in the corpus striatum was found to be lower (25% decrease) in the copper-treated group. Saturation studies of the striatal D-2 dopamine receptors using [3H]spiperone indicated that in copper-loaded animals the affinity was significantly increased threefold, whereas there was a trend for the number of receptors to decrease. When included in the radioligand binding assay, copper salts (Cu2+) inhibited specific [3H]spiperone binding to untreated corpora striata. The inhibition produced by copper was competitive with a significant decrease in affinity, the 50% effective concentration of Cu2+ was 21 to 24 microM, and the potency of dopamine agonists was also decreased. These results are discussed in relation to the mechanism by which copper affects dopaminergic function and to the use of copper-loaded rats as a model of Wilson's disease.