OBJECTIVE: To compare tranylcypromine (TCP) and phenelzine (PLZ), two well-established inhibitors of monoamine oxidase (MAO), and 2 of their analogues, 4-fluorotranylcypromine (FTCP) and N2-acetylphenelzine (AcPLZ) respectively, with regard to effects in the forced swimming test, a behavioural test used to screen for potential antidepressant drugs. METHODS: Mice were dropped individually into glass cylinders containing water. The duration of their immobility was scored during the last 4 minutes of the test. RESULTS: Except for TCP at high doses, none of the drugs demonstrated activity when administered alone. All 4 drugs were active when given in combination with clonidine, an effect thought to be the result of mixed action at 5-HT1A and 5-HT2 receptors and the noradrenergic system. 5-HT18 receptors do not seem to be implicated, as lithium did not potentiate the effect of any of the drugs. Quinine activation of AcPLZ suggests that this analogue acts on 5-HT3 receptors. CONCLUSIONS: FTCP and AcPLZ demonstrated anti-immobility activity in the forced swimming test when used in association clonidine. These findings confirm previous neurochemical findings suggesting that these drugs have antidepressant properties.