Increased synaptic serotonin (5-hydroxytryptamine) levels may underlie antidepressant-like effects of 3,4-methylenedioxymethamphetamine (MDMA) that may be more prominent in subjects with mood disturbance. The Flinders Sensitive Line (FSL) strain is an important animal model of depression. These rats are more immobile in the forced swimming test (FST), and their immobility is reversed by known antidepressants after prolonged administration. The objective of this study was to determine whether MDMA administration has a dose-dependent antidepressant-like effect in this animal model of depression. The effects of MDMA at 5 and 10 mg/kg following single and repeated administration were assessed in FSL rats using the FST. Sprague-Dawley rats were used as a control. During both FST sessions, saline-treated FSL rats were significantly more immobile than Sprague-Dawley rats (P<0.001). Acute MDMA administration had a dose-dependent antidepressant-like effect in FSL rats, which was most evident after 10 mg/kg. This effect was diminished after repeated administration. Methamphetamine 2 mg/kg, which was used as a positive control for locomotor activity induction, did not affect the depressive-like state in FSL rats. There were no changes in the cortical levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid after treatments. It is concluded that MDMA exhibited an antidepressant-like effect in FSL rats, which was most evident following acute administration.