The antidepressant-like effect induced by sigma 1-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test

The interaction of neuroactive steroids with the sigma (1)-receptor was inv estigated in Swiss mice submitted to the forced swimming test. The sigma (1 )-agonists igmesine and (+)-SKF-10,047 and the steroid dehydroepiandrostero ne sulfate (DHEAS) showed some antidepressant-like activity by shortening t he immobility time, these effects being blocked by the sigma (1)-antagonist BD1047 or progesterone. The sigma (1)-agonist PRE-084 or pregnenolone sulf ate failed to affect the immobility time. In adrenalectomized/ castrated (A dX/CX) mice, the effects of igmesine and DHEAS were significantly potentiat ed, and PRE-084 or pregnenolone sulfate induced significant decreases of im mobility 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 sigma (1)-recept or binding and neurosteroid levels was then examined in different brain str uctures, in terms of in vivo (+)-[H-3]SKF-10,047 binding to sigma (1)-sites and neurosteroids levels. In the hippocampus, but not in the cortex or cer ebellum, inhibition of in vivo (+)-[H-3]SKF-10,047 binding was measured in parallel to the extent of progesterone levels according to the endocrine co nditions. These data confirmed the antidepressant ability of sigma (1)-rece ptor agonists and revealed that the endogenous steroidal levels tonically i nterfere with the efficacy of the sigma (1)-system. It was observed that lo cal modifications in progesterone levels are directly related to the change s of in vivo sigma (1)-binding. Such observations may be of major importanc e in view of the therapeutic use of selective sigma (1)-agonists in depress ion.