OPIPRAMOL, A POTENT SIGMA-LIGAND, IS AN ANTIISCHEMIC AGENT - NEUROCHEMICAL EVIDENCE FOR AN INTERACTION WITH THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX INVIVO BY CEREBELLAR CGMP MEASUREMENTS

Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P < 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not oner protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol. © 1990.