Different roles of D-1 and D-2 dopamine receptors involved in locomotor activity of supersensitive mice.

Simultaneous stimulation of both D-1 and D-2 receptors is necessary to reverse reserpine-induced akinesia in mice. The effect of supersensitivity on locomotor function was studied in mice after treatment with reserpine for five days. The response of these animals to a mixed D-1/D-2 agonist, pergolide, or to a presynaptic dopamine (DA) releaser, amphetamine, was increased 3-fold, indicating behavioural supersensitivity. Under these conditions, both selective D-1 and D-2 dopamine receptor agonist (SKF 38393 and LY 171555, respectively), given separately, induced locomotor activity. The D-1 antagonist, SCH 23390, inhibited the effect of both SKF 38393 and LY 171555, whereas the DA synthesis inhibitor, alpha-methyl-p-tyrosine (AMPT), and the D-2 antagonist, sulpiride, only abolished the effect of LY 171555. Moreover, AMPT increased the response to SKF 38393 by 80%. The amphetamine-mediated responses were abolished by SCH 23390 whereas sulpiride did not block them. Thus, stimulation of the D-1 receptor seems crucial in supersensitive animals. In another set of experiments, AMPT was administered to mice pretreated with reserpine for five days in order to fully deplete DA stores. Low doses of LY 171555 reduced the response of these animals to SKF 38393 by 60% whereas higher doses potentiated it. This bimodal effect of LY 171555 was blocked by sulpiride. Since amphetamine was unable to reverse the reserpine-induced akinesia in these mice, we can conclude that the inhibitory effect of LY 171555 is not related to presynaptic inhibition of DA release.