UNCOMPETITIVE INHIBITION OF [H-3] 1,3-DI-O-TOLYL-GUANIDINE-DEFINED SIGMA-BINDING SITES BY DESIPRAMINE, PROPRANOLOL AND ALPRENOLOL IN RAT-BRAIN

Desipramine, imipramine, clomipramine, (-)-propranolol, (-)-alprenolol , (+/-)-pentazocine and risperidone caused a concentration-dependent i nhibition of 6 nM [H-3]DTG (1,3-di-o-tolylguanidine)-defined sigma (si gma) binding with K-i values of about 0.5-2.5 mu M in well-washed homo genates obtained from rat cerebral cortex, The saturation studies reve aled that the inhibition by desipramine (1-4 mu M), (-)-propranolol (1 mu M) and (-)-alprenolol (3 mu M) resulted from a reduction of the B- max value without alteration of the K-d of [H-3]DTG binding to the cor tex or hippocampus. In contrast, imipramine, (+/-)-pentazocine, clomip ramine and risperidone competitively attenuated the cortical or hippoc ampal [H-3]DTG binding. These findings demonstrate the uncompetitive i nhibition of [H-3]DTG binding by neuroactive drugs, thereby providing further support for the possible multiple regulation of cerebral sigma receptors. (C) 1997 Elsevier Science B.V.