Several serotonin3 (5-HT3) antagonists have been shown to attenuate the anxiogenic effects of the serotonergic agent, m-chlorophenylpiperazine (m-CPP), in animal models, but little data regarding possible effects of 5-HT3 antagonists on responses to m-CPP are available from studies in humans. Therefore, we studied the behavioral, physiological and neuroendocrine responses of 12 healthy volunteers to i.v. administered placebo and m-CPP (0.08 mg/kg), with and without i.v. pretreatment with the selective 5-HT3 antagonist, ondansetron (0.15 mg/kg). Compared to placebo, m-CPP given alone significantly increased ratings of anxiety and several other behavioral measures. m-CPP also produced statistically significant increases in temperature, systolic and diastolic blood pressure, heart rate, and in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and norepinephrine. Responses to ondansetron given alone were no different from those of placebo. Pretreatment with ondansetron did not affect peak behavioral responses to m-CPP, but was associated with a significantly earlier return to baseline levels of ratings of anxiety and functional deficit as well as a summary measure of overall behavioral effects. Following ondansetron pretreatment, the increases produced by m-CPP in systolic and diastolic blood pressure and heart rate were no longer significantly different from placebo. Ondansetron pretreatment significantly reduced their plasma cortisol response to m-CPP without affecting the other plasma hormone responses. Plasma concentrations of m-CPP were unaffected by ondansetron pretreatment. These findings suggest that in normal human subjects some behavioral, cardiovascular and neuroendocrine effects of m-CPP may be partially modulated by 5-HT3 receptor-mediated mechanisms.