A serotonergic mechanism of the prolactin-stimulating action of metoclopramide.

The PRL-stimulating effect of metoclopramide (2-methoxy-5-chloroprocainamide) was examined in normal and adrenalectomized male rats pretreated with DL-p-chlorophenylalanine methyl ester (PCPA), an inhibitor of serotonin biosynthesis. PCPA significantly reduced the hypothalamic content of serotonin, increased basal PRL in adrenalectomized rats but not in controls, and potentiated PRL elevation in response to metoclopramide. In the PCPA-pretreated groups, the maximal PRL response to metoclopramide was 60% and 85% higher than that in the saline controls of normal and adrenalectomized rats, respectively. PCPA did not enhance the PRL-stimulating effect of haloperidol, a well established dopamine antagonist, L-alpha-Methyl-p-tyrosine pretreatment in rats depleted hypothalamic dopamine without any change in serotonin and elevated basal PRL, but failed to show an additive effect with metoclopramide's action on serum PRL. Rats pretreated with mianserin, a specific brain serotonin receptor blocker, attenuated PRL elevation in response to low doses of metoclopramide but produced the same response to high doses of metoclopramide as the control rats. These data indicated that metoclopramide stimulated rats pituitary PRL secretion by a serotonergic mechanism in addition to its dopamine antagonist properties.