alpha-methyldopa reduces locomotor activity in rats via its metabolite, alpha-methylnorepinephrine, acting on alpha 2-adrenoceptors.

The decrease in locomotor activity in rats caused by alpha-methyldopa (alpha-MD), 400 mg/kg p.o. was antagonized by treatment with yohimbine, a selective antagonist of alpha 2-adrenoceptors. Effective doses of yohimbine ranged from 0.25--2.0 mg/kg s.c., whereas yohimbine at 0.125 mg/kg did not significantly affect the decrease in locomotor activity caused by alpha-MD. Similar results were obtained in studies on the interaction between clonidine injected intracisternally and various doses of yohimbine given s.c., except that the higher doses of yohimbine completely blocked the depression of locomotor activity caused by clonidine, but not by alpha-MD. The depression of motor activity following alpha-MD was not offset by prazosin, a preferential alpha 1-antagonist. At the same doses that failed to alter the action of alpha-MD, prazosin was effective in antagonizing the increase in motor activity resulting from intracisternally injected methoxamine, a selective agonist, at alpha 1-receptors. Treatment with FLA-63, using a regimen that was shown to inhibit dopamine-beta-hydroxylase in brain, caused a diminution in the ability of alpha-MD to depress locomotor activity. These findings indicate that alpha-MD reduces locomotor activity in the rat at least in part via the formation of alpha-methylnorepinephrine which acts on alpha 2-adrenoceptors.