This study investigates the effects of methylenedioxymethamphetamine (MDMA) and amphetamine on monoamine release from rat superfused brain slices in both the presence and absence of vesicular stores of transmitter. MDMA caused the release of radioactivity from slices incubated with [3H]5-hydroxytryptamine, [3H]noradrenaline or [3H]dopamine with EC50 values of 1.9 mumol/l (95% confidence limits 1.5-2.3 mumol/l), 4.5 mumol/l (2.3-8.7 mumol/l), and greater than 30 mumol/l, respectively. In contrast, amphetamine (0.1-300 mumol/l) was more effective in releasing radioactivity from slices incubated with [3H]dopamine than [3H]noradrenaline or [3H]5-hydroxytryptamine. When Ca2+ was excluded from the superfusion fluid, the MDMA-induced release of radioactivity from slices incubated with [3H]dopamine was unaltered, but that from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine was enhanced. MDMA (10 mumol/l) facilitated the stimulation-induced (5 Hz, 1 min) outflow of radioactivity from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine to 7.5-fold and 2.1-fold of control values, respectively, but had no effect on that from slices incubated with [3H]dopamine. Amphetamine (1 mumol/l) increased the stimulation-induced outflow from slices incubated with [3H]noradrenaline, but not that from slices incubated with [3H]5-hydroxytryptamine or [3H]dopamine. Inhibition of monoamine oxidase by a 30-min incubation with pargyline (100 mumol/l) enhanced the releasing action of MDMA on all three monoamines. Pargyline (100 mumol/l) also enhanced the facilitation caused by MDMA, of the stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline, [3H]5-hydroxytryptamine or [3H]dopamine. In some experiments, slices were obtained from reserpinised rats (2.5 mg/kg s.c. 24 h prior) and pre-exposed for 30 min to the monoamine oxidase inhibitor parglyine (100 mumol/l). Under these conditions, electrical stimulation evoked a small residual stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline, and failed to evoke an outflow of radioactivity from slices incubated with [3H]5-hydroxytryptamine or [3H]dopamine. However, a Ca(2+)-dependent stimulation-induced outflow of radioactivity was evoked in the presence of either MDMA (10 mumol/l) or amphetamine (1 mumol/l) from slices incubated with either [3H]dopamine or [3H]noradrenaline, but not from slices incubated with [3H]5-hydroxytryptamine. The stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline was enhanced in the presence of desipramine (1 mumol/l), however this enhancement was less than that caused by 10 mumol/l MDMA or 1 mumol/l amphetamine. The Ca(2+)-dependent response to electrical stimulation in the presence of MDMA from slices incubated with [3H]noradrenaline was greatly reduced when rats were pretreated with a higher dose of reserpine (10 mg/kg s.c.).(ABSTRACT TRUNCATED AT 400 WORDS)