The effects of two selective 5-HT-releasing agents, 4-methylthioamphetamine (MTA) and 5-methoxy-6-methyl-2-aminoindan (MMAI), on the extracellular 5-HT concentration in the dorsal hippocampus was determined by microdialysis in anesthetized rats. After i.p. administration of 1 or 5 mg/kg of either compound, a rapid and significant increase of 5-HT basal release was observed. MTA (5 mg/kg) induced a maximal increase of about 2000% over the basal value 40 min after injection, which declined slowly, whereas MMAI (5 mg/kg) induced a maximal response of about 1350% which showed a rapid decline. Monoamine oxidase-A inhibitory properties of MTA, and MMAI's lack of similar properties might account for the difference between the two compounds. In agreement with previous information, a much lower increase in hippocampal 5-HT was observed in response to systemic fluoxetine. This difference in the magnitude of the response after MTA or MMAI and fluoxetine indicates that different mechanisms of action are operating. Based on evidence showing that an acute enhancement of 5-HT neurotransmission might result in the rapid appearance of therapeutic effects of serotonergic antidepressants, we suggest that MTA and MMAI might serve as leads for a novel family of compounds with a short onset of action useful for treating depression.