Venlafaxine, an antidepressant with serotonin and noradrenaline reuptake inhibiting properties, has been reported to reduce acquisition (but not maintenance) of heroin intravenous self-administration (IVSA) in rats. The present study investigated whether this phase-dependent effect is due to an antidepressant-induced attenuation of the rewarding effect of heroin, as assessed in the conditioned place preference (CPP) paradigm. In order to study the effects of venlafaxine and the tricyclic antidepressant desipramine on acquisition and expression of heroin CPP, both compounds were administered prior to the conditioning sessions (together with heroin), or prior to the expression test after conditioning, respectively. As clinical evidence indicates that antidepressants require repeated administration for full efficacy, additional experiments were performed in which both antidepressants were administered for 2 weeks prior to conditioning, or for 1 week prior to the expression test, respectively. When tested alone, heroin [0.05-3.16 mg/kg intraperitoneally (i.p.)] produced a dose-dependent CPP, whereas the antidepressants (1-21.5 mg/kg i.p.) produced neither a CPP nor a conditioned place aversion (CPA). For both antidepressants (10 mg/kg i.p.), neither acute nor repeated pretreatment affected acquisition or expression of heroin (0.5 mg/kg) CPP. Thus, the present study does not support the hypothesis that the previously observed attenuation of acquisition of heroin IVSA by venlafaxine is due to an antidepressant-induced attenuation of the rewarding effect of heroin. It is conceivable, however, that the rewarding effect of the 0.5 mg/kg dose of heroin was too pronounced to be susceptible to modulation by antidepressants. Alternatively, the modulation of acquisition of heroin IVSA in the previous study may be related to mechanisms that cannot be modelled with the CPP paradigm.