Sigma (σ) and phencyclidine (PCP) receptor ligands, apart from their main effects on σ receptors and NMDA receptor-mediated neurotransmission, have been found to interact with catecholamine systems in several central and peripheral tissues. In the present study the binding profile of [ 3 H]nisoxetine ([ 3 H]NIS), a selective marker of the noradrenaline transporter, has been characterized in rat vas deferens membranes to further study its modulation by a number of characteristic σ and PCP ligands. The binding of [ 3 H]NIS was found to be of high affinity (K d = 1.63 ± 0.36 nM), saturable, sodium-dependent and to a single population of binding sites (n H = 1.003 ± 0.017). The maximal binding capacity was 1,625 ± 500 fmol/mg of protein. Kinetic experiments gave a k + 1 of 3.9 10 7 min - 1 M - 1 and a k - 1 of 0.005 min - 1 . The [ 3 H]NIS binding was totally inhibited, with IC 5 0 values in the micromolar range, by all the σ and PCP ligands tested, with the following order of potency: haloperidol > dextromethorphan > dizocilpine > dextrorphan > (+)-3-PPP > PCP > tenocyclidine. This order correlates well with that described in other tissues using [ 3 H]desmethylimipramine. The inhibition by all these compounds, except that of (+)-3-PPP, was competitive. These results suggest that σ and PCP ligands bind, at low micromolar concentrations, to a site in the noradrenaline transporter that is labelled by [ 3 H]NIS.