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 investigated in Swiss mice submitted to the forced swimming test. The sigma(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 sigma(1)-antagonist BD1047 or progesterone. The sigma(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 sigma(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 sigma(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 sigma(1)-receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the sigma(1)-system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo sigma(1)-binding. Such observations may be of major importance in view of the therapeutic use of selective sigma(1)-agonists in depression.
Urani
A
A
Behavioral Neuropharmacology Group, Institut National de la Santé et de la Recherche Médicale Unité 336, Montpellier, France.
Roman
F J
FJ
Phan
V L
VL
Su
T P
TP
Maurice
T
T
D000315:Adrenalectomy; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D011863:Radioimmunoassay; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013256:Steroids / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D013550:Swimming / Q000523:psychology
D000928:Antidepressive Agents; D017465:Receptors, Opioid, delta; D013256:Steroids; D003687:Dehydroepiandrosterone; C012134:SK&F 10047; D010620:Phenazocine