The antidepressant-like effect induced by the sigma₁ (σ₁) receptor agonist igmesine involves modulation of intracellular calcium mobilization

Abstract

Rationale. Activation of the neuronal sigma₁ (σ₁) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, σ₁ agonists modulate learning, response to stress and depression. In particular, the selective σ₁ agonist igmesine reduced immobility in the forced swimming test.

Objectives and methods. We investigated the effect of modulators of Ca²⁺ influx and mobilization, administered intracerebroventricularly at doses ineffective alone, on the igmesine effect. The tricyclic antidepressant desipramine was also studied for comparison.

Results. The calcium chelator EGTA blocked both igmesine and desipramine-induced decreases of immobility duration, indicating the importance of extracellular Ca²⁺ influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the σ₁ agonist effect. Verapamil, an L-type VDCC antagonist or ω-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (–)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca²⁺ stores is involved selectively in the effect mediated by the σ₁ receptor, since the membrane permeable intracellular Ca²⁺ chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP₃) receptor-sensitive Ca²⁺ pools appeared primarily involved, rather than Ca²⁺/caffeine-sensitive Ca²⁺ pools. Indeed, the InsP₃ receptor positive modulator bradykinin potentiated, whereas the InsP₃ receptor antagonist xestospongin C blocked the igmesine effect. The ryanodine receptor agonist caffeine failed to affect the efficacy of igmesine, whereas the antagonist ryanodine reduced it.

Conclusions. The σ₁ receptor-mediated behavioral effect is dependent not only on rapid Ca²⁺ influx, as observed for a classical antidepressant, but also on intracellular Ca²⁺ mobilization.