title: Opipramol, a potent sigma ligand, is an anti-ischemic agent: neurochemical evidence for an interaction with the N-methyl-D-aspartate receptor complex in vivo by cerebellar cGMP measurements.
abstract: Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 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 offer 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.
authors.affiliation: CNS Diseases Research, G.D. Searle & Co., Monsanto Company, St Louis, Missouri 63198.
authors.forename: T S
authors.initials: TS
authors.lastname: Rao
authors.forename: J A
authors.initials: JA
authors.lastname: Cler
authors.forename: S J
authors.initials: SJ
authors.lastname: Mick
authors.forename: D M
authors.initials: DM
authors.lastname: Ragan
authors.forename: T H
authors.initials: TH
authors.lastname: Lanthorn
authors.forename: P C
authors.initials: PC
authors.lastname: Contreras
authors.forename: S
authors.initials: S
authors.lastname: Iyengar
authors.forename: P L
authors.initials: PL
authors.lastname: Wood
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D008024:Ligands; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009888:Opipramol / Q000494:pharmacology / Q000627:therapeutic use*; D010433:Pentylenetetrazole / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017480:Receptors, sigma
chemical_list: D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D017480:Receptors, sigma; D008694:Methamphetamine; D009888:Opipramol; D006152:Cyclic GMP; D010433:Pentylenetetrazole