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

Abstract

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.

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“…Most previous studies have used the 2-day forced-swim procedure to examine the antidepressant-like effects of drugs (Cryan et al, 2005;Villard et al, 2011). This procedure consists of an initial 10e15-min pre-swim session conducted on day 1 followed by a 6-min swim test session conducted 24 h later.…”

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“…s 1 Rs modulate depression-related processes such as the serotonergic neurotransmission in the dorsal raphe nucleus (6). Antidepressants such as fluoxetine, fluvoxamine, or imipramine present high to moderate affinity for the s 1 R (affinity constant [K i ], 20-200 nM) (7). Repeated treatment with imipramine or fluoxetine and dl-pentazocine, a classic s 1 R ligand, caused a decrease of s 1 R density in the striatum, hippocampus, and cerebral cortex of rats (8,9).…”

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