Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant

Igmesine is a selective sigma (sigma (1)) ligand that was reported to exert antidepressant action through an unknown mechanism of action. A number of neurochemical measures were taken in this study in efforts to understand it s mode of action. Following 21-day drug treatments, the actions of igmesine on a number of neurochemical measures were investigated. Data obtained sho wed significant decreases in the densities of beta -adrenergic but not 5-HT 1A, sigma (1) and GABA(B) receptors in fluoxetine (18%), desipramine (DMI, 32%) and igmesine (20%)-treated groups when compared with control. Tyrosine hydroxylase (TH) activity was significantly (30-32%) reduced in all treate d groups. Further, fluoxetine and DMI excluding the igmesine-treated groups showed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) ne uronal uptake, respectively. Following acute treatment, igmesine lacked act ivity for monoamine oxidase (MAO) A or B (IC50>10 muM). In in vivo studies, at behaviorally active doses, igmesine showed weak effects: on the NE upta ke but lacked activity in altering 5-HT and DA synthesis or antagonizing se lective drug-induced depletion of monoamine neuronal uptake. N-methyl-D-asp artate (NMDA)-induced increases in cGMP was blocked by igmesine indicating that igmesine may interfere with the NMDA receptor/nitric oxide synthase/cG MP pathway. Although it appears that part of the pharmacological actions of igmesine is mediated by the monoaminergic system, there is still need to e xplore other possible mechanisms of antidepressant action. (C) 2001 Elsevie r Science Ltd. All rights reserved.