Recently much research interest has focused on the possible therapeutic uses of sigma-receptor ligands in psychiatric and neurodegenerative disorders. In the present study, the potential neuroprotective effects of chronic (52 days) administration of (+) cinnamyl-l-phenyl-l-N-methyl-N-cyclo propylene (JO 1784) (1 and 3 mg/kg subcutaneously), a potent and selective sigma receptor ligand, were assessed in the trimethyltin (8 mg/kg intraperitoneally) model of memory dysfunction. JO 1784 (3 mg/kg subcutaneously) prevented the trimethyltin-induced deficits in locomotor activity, passive avoidance and radial maze performance, while the lower dose of JO 1784 had little or no effect. Trimethyltin was also shown to produce a marked reduction in the binding of [3H] (+)-pentazocine to sigma-receptor sites in limbic brain structures, as detected by quantitative autoradiography, which was particularly evident in the hippocampal pyramidal cells. JO 1784 (3 mg/kg subcutaneously) successfully attenuated this loss of [3H] (+)-pentazocine binding sites in the hippocampus (CA1, CA3 and CA4 regions) and in the substantia innominata. This neuroprotective effect of JO 1784 in the trimethyltin model would seem to be related to the modulatory effects of this sigma ligand on trimethyltin-induced glutamate neurotoxicity.