THE SIGMA-LIGAND JO-1784 PREVENTS TRIMETHYLTIN-INDUCED BEHAVIORAL ANDSIGMA-RECEPTOR DYSFUNCTION IN THE RAT

Recently much research interest has focused on the possible therapeuti c 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-1-phenyl-1-N-meth yl-N-cyclo propylene (JO 1784) (1 and 3 mg/kg subcutaneously), a poten t and selective sigma receptor ligand, were assessed in the trimethylt in (8 mg/kg intraperitoneally) model of memory dysfunction. JO 1784 (3 mg/kg subcutaneously) prevented the trimethylin-induced deficits in l ocomotor activity, passive avoidance and radial maze performance, whil e the lower dose of JO 1784 had little or no effect. Trimethyltin was also shown to produce a marked reduction in the binding of [H-3] (+)-p entazocine to sigma-receptor sites in limbic brain structures, as dete cted by quantitative autoradiography, which was particularly evident i n the hippocampal pyramidal cells. JO 1784 (3 mg/kg subcutaneously) su ccessfully attenuated this loss of [H-3] (+)-pentazocine binding sites in the hippocampus (CA(1), CA(3) and CA(4) regions) and in the substa ntia innominata. This neuroprotective effect of JO 1784 in the trimeth yltin model would seem to be related to the modulatory effects of this sigma ligand on trimethyltin-induced glutamate neurotoxicity.