Pharmacological characteristics of a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), milnacipran, in modulation of the synaptic plasticity were investigated. Milnacipran (30 mg/kg, i.p.) suppressed the long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Milnacipran-induced suppression was reversed by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, i.v.) or the alpha1-adrenoceptor antagonist prazosin (1 and 10 microg/rat, i.c.v.). The alpha2-adrenoceptor antagonist idazoxan (5 mg/kg, i.p.) did not influence the milnacipran-induced synaptic responses. These data suggest that the inhibitory effects of milnacipran on LTP induction are mediated via both 5-HT1A receptors and alpha1-adrenoceptors. In other words, functional interaction between the serotonergic and noradrenergic neuronal systems is involved in alteration of the hippocampal synaptic plasticity, which may be implicated in the SNRI-induced therapeutic effect on psychiatric disorders.