Pharmacological Interaction With the Sigma1 (σ1)-Receptor in the Acute Behavioral Effects of Antidepressants (original) (raw)

Abstract

Selective agonists of the sigma-1 (_σ_1) ligand–operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. _σ_1-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the _σ_1-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS). The involvement of the _σ_1-receptor was examined using a co-treatment with the _σ_1-antagonist BD1047 or using _σ_1-knockout (KO) mice. Igmesine but not PRE-084 decreased FST immobility. The SSRI fluoxetine and sertraline, but not fluvoxamine, and the tricyclic antidepressants imipramine, desipramine, and amitriptyline were also effective. Only the effect of igmesine was blocked by BD1047 or in _σ_1-KO mice. Igmesine, PRE-084, fluvoxamine, and sertraline decreased the CFS immobility in a BD1047- and _σ_1-KO–sensitive manner. Among tricyclics, only amitriptyline was effective and its effect was unaffected by BD1047 or in _σ_1-KO mice. The behavioral effects induced by mixed _σ_1-receptor/SSRI antidepressants, like fluvoxamine or sertraline, may therefore involve a non-selective action at both targets. Moreover, the CFS appears to more reliably uncover a _σ_1 pharmacological component in antidepressant screening.