SIGMA-BINDING PARAMETERS IN DEVELOPING RATS PREDICT BEHAVIORAL EFFICACY OF A SIGMA-LIGAND

The relationship between sigma binding and the behavioral efficacy of a selective sigma ligand was examined in rats of varying ages (30, 45, 60, 75, 90, and 150 days old). Scatchard analyses of the binding of t he sigma radioligand [H-3]1,3-di-o-tolylguanidine ([H-3]DTG) to brain membranes revealed significant age-related differences in binding to b oth crude synaptosomal and microsomal fractions. The functional signif icance of these developmental changes in sigma ligand binding was stud ied by determining the postural effects of rubral microinjections of D TG in age-matched littermates of rats used in the binding studies. The degree of dystonia produced by a single dose of DTG was significantly correlated with the amount of [H-3]DTG bound to rat brain synaptosoma l membranes at low but not at high concentrations. No significant corr elation between binding to the microsomal fraction and drug efficacy w as observed. These experimental results were in good agreement with pr edicted amounts bound as estimated from a Scatchard analysis of the da ta. The results suggest that sigma binding sites found in brain synapt osomal membranes are functional receptors involved in the control of m ovement and posture.