The Interaction of the Serotonergic and Dopaminergic Systems on Prolactin Secretion in the Rat: The Mechanism of Action of the “Specific” Serotonin Receptor Antagonist, Methysergide*

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Abstract
Mechanisms governing PRL secretion by the serotonergic system and the inhibitory effects of methysergide were analyzed. 5-Hydroxytryptophan (5-HTP) injection into rats greatly increased serum PRL concentration. In vitro, the pituitary gland from these rats synthesized and secreted amounts of PRL similar to those produced by nontreated rats. Interaction with the dopaminergic system was investigated by testing the sensitivity of these pituitary glands in vitro to dopamine. In vitro, a comparable inhibitory effect of 500 nM dopamine on PRL secretion was observed in both control and 5-HTP-injected rats. A significant increase in PRL synthesis was observed in glands from 5-HTP-treated rats when the pituitaries were incubated in the presence of dopamine. Neither 5-HTP nor serotonin had a direct in vitro effect on PRL secretion. Serotonin precursors possibly exert their stimulatory effect on PRL secretion via the hypothalamus and not at the pituitary gland. Methysergide administration caused an early increase in serum PRL; however, after 2-4 h, a significant inhibitory effect was produced by the drug. The in vitro secretion of PRL was greatly decreased by the prior injection of methysergide. This was completely blocked by the coadministration of haloperidol. Dopamine was less able to decrease the in vitro secretion of PRL when the animals were injected with methysergide 15 min earlier. Methysergide had no direct in vitro effect on PRL secretion. It completely blocked dopamine-mediated inhibition of PRL secretion. Methergine, the demethylated metabolite of methysergide, significantly inhibited in vitro PRL secretion and this effect was completely blocked by coincubation with haloperidol. These data support the concept that serotonin is stimulatory to the brain-neuroendocrine system which stimulates the secretion of PRL. The mechanisms through which serotonin and methysergide act to modify PRL secretion are very complex and may act by influencing the dopaminergic system. The initial response after methysergide injection is stimulatory to PRL secretion by blockade of the dopamine receptor, and subsequently, the metabolites of the drug inhibit secretion of the hormone by stimulating the pituitary dopaminergic system.