Involvement of sigma-1 receptor modulation in the antidepressant action of venlafaxine

Multiple lines of investigation have explored the role of sigma receptors in mental depression. Sigma receptors particularly, sigma-1 subtype is known to modulate the release of various catecholamines in the brain and may play, in some way, a role in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the antidepressant-like effect of venlafaxine (dual serotonin and norepinephrine reuptake inhibitor) in the mouse forced swim test (FST). Immobility period in the forced swim test was registered for a total period of 6 min. Venlafaxine produced dose-dependent (4-16 mg/kg, i.p.) reduction in immobility period. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergism with subeffective dose of venlafaxine (2 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of venlafaxine (8 mg/kg i.p.). The various modulators used in the study did not produce any changes in locomotor activity per se except venlafaxine which at higher dose (16 mg/kg, i.p.) significantly increased the locomotor activity in mice. The results for the first time demonstrated that the anti-immobility effects of venlafaxine in the FST possibly involve an interaction with sigma-1 receptors.