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 the sigma radioligand [3H]1,3-di-o-tolylguanidine ([3H]DTG) to brain membranes revealed significant age-related differences in binding to both crude synaptosomal and microsomal fractions. The functional significance of these developmental changes in sigma ligand binding was studied by determining the postural effects of rubral microinjections of DTG 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 [3H]DTG bound to rat brain synaptosomal membranes at low but not at high concentrations. No significant correlation between binding to the microsomal fraction and drug efficacy was observed. These experimental results were in good agreement with predicted amounts bound as estimated from a Scatchard analysis of the data. The results suggest that sigma binding sites found in brain synaptosomal membranes are functional receptors involved in the control of movement and posture.