The Antidepressant-Like Effect Induced by ς1-Receptor Agonists and Neuroactive Steroids in Mice Submitted to the Forced Swimming Test

The interaction of neuroactive steroids with the ς 1 -receptor was investigated in Swiss mice submitted to the forced swimming test. The ς 1 -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 ς 1 -antagonist BD1047 or progesterone. The ς 1 -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 ς 1 -receptor binding and neurosteroid levels was then examined in different brain structures, in terms of in vivo (+)-[ 3 H]SKF-10,047 binding to ς 1 -sites and neurosteroids levels. In the hippocampus, but not in the cortex or cerebellum, inhibition of in vivo (+)-[ 3 H]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 ς 1 -receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the ς 1 -system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo ς 1 -binding. Such observations may be of major importance in view of the therapeutic use of selective ς 1 -agonists in depression.