The antidepressant-like effect induced by σ1-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test

Abstract

The interaction of neuroactive steroids with the σ1-receptor was investigated in Swiss mice submitted to the forced swimming test. The σ1-agonists igmesine and (+)-SKF-10,047 and the steroid dehydroepiandrosterone sulfate (DHEAS) showed some antidepressant-like activity by shortening the immobility time, these effects being blocked by the σ1-antagonist BD1047 or progesterone. The σ1-agonist PRE-084 or pregnenolone sulfate failed to affect the immobility time. In adrenalectomized/castrated (AdX/CX) mice, the effects of igmesine and DHEAS were significantly potentiated, and PRE-084 or pregnenolone sulfate induced significant decreases of immobility time. The augmented effects in AdX/CX were fully blocked by BD1047. The effects of the classical antidepressants, desipramine or fluoxetine, were unchanged in AdX/CX mice. The effect of stress on the σ1-receptor binding and neurosteroid levels was then examined in different brain structures, in terms of in vivo (+)-[3H]SKF-10,047 binding to σ1-sites and neurosteroids levels. In the hippocampus, but not in the cortex or cerebellum, inhibition of in vivo (+)-[3H]SKF-10,047 binding was measured in parallel to the extent of progesterone levels according to the endocrine conditions. These data confirmed the antidepressant ability of σ1-receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the σ1-system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo σ1-binding. Such observations may be of major importance in view of the therapeutic use of selective σ1-agonists in depression.