Male and female rats were compared with respect to alterations in prolactin secretion induced by the serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The dose-response curves after 8-OH-DPAT were irregular and had different shapes in the two sexes. In males, 0.1 and 0.3 mg/kg enhanced serum prolactin concentrations to about 200% of control values, whereas higher doses (1 and 3 mg/kg) had no effect on prolactin release. In females, in contrast, 0.1 mg/kg of 8-OH-DPAT tended to decrease serum levels of prolactin, while 0.3, 1, and 3 mg/kg elevated them in a dose dependent manner to maximally 700% of control values. The serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (5 mg/kg), too, caused increased prolactin release in both sexes, and, again, females responded more forcefully. In males, but not in females, pretreatment with 8-OH-DPAT (1 mg/kg) reduced the 5-MeODMT-induced elevation of serum prolactin levels. The mechanism underlying the sexually differentiated effects of 8-OH-DPAT on prolactin secretion is discussed.