The antidepressant-like effect induced by the sigma(1) (sigma(1)) receptor agonist igmesine involves modulation of intracellular calcium mobilization.
BACKGROUND
Activation of the neuronal sigma(1) (sigma(1)) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, sigma(1) agonists modulate learning, response to stress and depression. In particular, the selective sigma(1) agonist igmesine reduced immobility in the forced swimming test.


OBJECTIVE
We investigated the effect of modulators of Ca(2+) 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 Ca(2+) influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the sigma(1) agonist effect. Verapamil, an L-type VDCC antagonist or omega-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (-)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca(2+) stores is involved selectively in the effect mediated by the sigma(1) receptor, since the membrane permeable intracellular Ca(2+) chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP(3)) receptor-sensitive Ca(2+) pools appeared primarily involved, rather than Ca(2+)/caffeine-sensitive Ca(2+) pools. Indeed, the InsP(3) receptor positive modulator bradykinin potentiated, whereas the InsP(3) 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 sigma(1) receptor-mediated behavioral effect is dependent not only on rapid Ca(2+) influx, as observed for a classical antidepressant, but also on intracellular Ca(2+) mobilization.
Département de Biochimie/Enzymologie, Pfizer GRD-Fresnes, 3/9, rue de la Loge, BP 100, 94265 Fresnes Cedex, France.
Alexandre
A
Urani
Pascal
P
Romieu
Elodie
E
Portales-Casamar
François J
FJ
Roman
Tangui
T
Maurice
D000315:Adrenalectomy; D000818:Animals; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D003863:Depression / Q000523:psychology; D003891:Desipramine / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009919:Orchiectomy; D017480:Receptors, sigma / Q000819:agonists*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D000097605:Sigma-1 Receptor
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D002118:Calcium; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D002614:Chelating Agents; D002934:Cinnamates; D003521:Cyclopropanes; D003891:Desipramine; D017480:Receptors, sigma; D019837:Ryanodine Receptor Calcium Release Channel; D000097605:Sigma-1 Receptor; C065310:igmesine