Enhanced antidepressant efficacy of σ₁ receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid-(1-40) protein

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.