The involvement of serotonin (5-HT) in oxytocin secretion was investigated in this study. Pharmacologic agents that influence serotonergic transmission were administered to conscious unrestrained male rats 30 min prior to sacrifice and plasma oxytocin concentration was measured by radioimmunoassay. The d- and l-stereoisomers of the 5-HT releaser fenfluramine significantly increased plasma oxytocin in a dose-dependent manner. Oxytocin secretion was more potently stimulated by d-fenfluramine than by l-fenfluramine. The 5-HT releaser p-chloroamphetamine also increased plasma oxytocin. The following 5-HT agonists increased plasma oxytocin concentration: the 5-HT1&2 agonist m-chlorophenyl-piperazine [10-20 mg/kg intraperitoneally (i.p.)], the 5-HT1C&2 agonist 1-(2,5-dimethoxy-4-l-phenyl)-2-aminopropane (0.5-2.0 mg/kg i.p.) and the 5-HT1&2 agonist 1-piperazinyl-6-chloropyrazine (10 mg/kg i.p.). In contrast, the 5-HT1AB agonist 5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole (0.2-5.0 mg/kg i.p.) did not increase oxytocin secretion. Pretreatment with the 5-HT1C&2 antagonist, 6-(2-(4-[bis(4-fluorophenyl)methylene]-1-piperidinyl)ethyl)-7-methyl-5H- thiazolo(3(1)2-a)pyrimidin-5-one [2.5 mg/kg subcutaneously (s.c.)], 60 min before injection of 1-piperazinyl-6-chloropyrazine attenuated, but did not completely block, 1-piperazinyl-6-chloropyrazine-induced secretion of oxytocin. Both low and high (0.01 and 0.1 mg/kg s.c.) doses of 6-(2-(4-[bis(4-fluorophenyl)methylene]-1-piperidinyl)ethyl)-7-methyl-5H- thiazolo(3(1)2-a)pyrimidin-5-one or the 5-HT2 antagonist spiperone inhibited the 1-(2,5-dimethoxy-4-l-phenyl)-2-aminopropane-induced increases in plasma oxytocin. These studies provide evidence that enhanced serotonergic transmission stimulates oxytocin secretion and that 5-HT2 receptors contribute to this effect.