Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective σ1 receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the σ1 receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the β-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in β-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in β-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in β-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after β-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of β-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the β-amyloid infusion. The σ 1 receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the β-amyloid toxicity. The present study suggests that σ1 receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.
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