Vol. 298, Issue 3, 1269-1279, September 2001

The Antidepressant-Like Effect Induced by ₁-Receptor Agonists and Neuroactive Steroids in Mice Submitted to the Forced Swimming Test

Alexandre Urani , François J. Roman, Vân-Ly Phan, Tsung-Ping Su and Tangui Maurice

Behavioral Neuropharmacology Group, Institut National de la Santé et de la Recherche Médicale Unité 336, Montpellier, France (A.U., V.-L.P., T.M.); Pfizer-Fresnes, Fresnes, France (A.U., F.R.); and Cellular Pathobiology Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.-P.S.).

The interaction of neuroactive steroids with the ₁-receptor was investigated in Swiss mice submitted to the forced swimming test. The 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 ₁-antagonist BD1047 or progesterone. The 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 ₁-receptor binding and neurosteroid levels was then examined in different brain structures, in terms of in vivo (+)-[³H]SKF-10,047 binding to ₁-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 ₁-receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the ₁-system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo ₁-binding. Such observations may be of major importance in view of the therapeutic use of selective ₁-agonists in depression.