The effects of new sigma (σ) receptor ligands, PB190 and PB212, in the models predictive of antidepressant activity.

Background: A number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress). The objective of the present study was to find out whether PB190 and PB212, new σ1 receptor ligands, show the effects in some models predictive of antidepressant activity.

Methods: The impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP3 pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2.

Results: In the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ1-receptor antagonist. The in vitro studies indicated that Ca(2+)-response was increased by 1μM PB190, like by the σ1-agonist (+)-pentazocine, while 1 μM PB212 behaved line σ1-antagonist, BD1063. On the other hand, 100 μM PB190 negatively affected the Ca(2+)-response after bradykinin.

Conclusions: The obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ1-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ1-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.