3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is associated with increases in core body temperature (T(C)) and depressive mood states in users. Flinders Sensitive Line (FSL) rats represent a rat model of depression originally bred from Sprague-Dawley (SD) rats. They are more sensitive to both muscarinic and serotonergic agonists and have altered thermoregulatory responses to various drugs. To examine the link between MDMA and depression, eight FSL and eight SD rats were administered saline and 5 and 7.5 mg/kg MDMA. Immediately following administration, rats were confined to an area with an ambient temperature (T(A)) of 30 ± 1°C for 30 minutes before being allowed access to a thermal gradient for four hours. The brains were removed one week after final dose of MDMA and concentrations of serotonin and dopamine were measured. Treatment with MDMA at both doses led to a higher T(C) in the FSL rats than the SD rats at high T(A) (P < 0.01). Fatalities due to hyperthermia occurred in the FSL rats after both doses, whereas all but one of the SD rats recovered well. Heart rate was also much higher after MDMA in the FSL rats throughout the experiments. The FSL rats showed significant decreases in all transmitters measured (P < 0.05). These differences between strains were not accounted for by altered blood or brain concentrations of MDMA. The results indicate that the FSL rats may be more susceptible to developing MDMA-induced hyperthermia and possible damage to the brain. These findings may be of importance to human users of MDMA who also have depression.