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

Alexandre Urani, Pascal Romieu, François J. Roman, Kiyofumi Yamada, Yukihiro Noda, Hiroyuki Kamei, Hung Manh Tran, Taku Nagai, Toshitaka Nabeshima, Tangui Maurice

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)151-161
Number of pages11
JournalEuropean Journal of Pharmacology
Volume486
Issue number2
DOIs
Publication statusPublished - 20-02-2004
Externally publishedYes

Fingerprint

Intraventricular Infusions
Amyloid
Antidepressive Agents
Dehydroepiandrosterone Sulfate
Proteins
Progesterone
Depression
Pregnenolone
Brain
Exercise Test
Neurodegenerative Diseases
Fear
Neurotransmitter Agents
Hippocampus
Alzheimer Disease
Esters
Animal Models
Steroids
Pharmacology
Neurons

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Urani, Alexandre ; Romieu, Pascal ; Roman, François J. ; Yamada, Kiyofumi ; Noda, Yukihiro ; Kamei, Hiroyuki ; Manh Tran, Hung ; Nagai, Taku ; Nabeshima, Toshitaka ; Maurice, Tangui. / Enhanced antidepressant efficacy of σ1 receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid-(1-40) protein. In: European Journal of Pharmacology. 2004 ; Vol. 486, No. 2. pp. 151-161.
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Enhanced antidepressant efficacy of σ1 receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid-(1-40) protein. / Urani, Alexandre; Romieu, Pascal; Roman, François J.; Yamada, Kiyofumi; Noda, Yukihiro; Kamei, Hiroyuki; Manh Tran, Hung; Nagai, Taku; Nabeshima, Toshitaka; Maurice, Tangui.

In: European Journal of Pharmacology, Vol. 486, No. 2, 20.02.2004, p. 151-161.

Research output: Contribution to journalArticle

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AU - Urani, Alexandre

AU - Romieu, Pascal

AU - Roman, François J.

AU - Yamada, Kiyofumi

AU - Noda, Yukihiro

AU - Kamei, Hiroyuki

AU - Manh Tran, Hung

AU - Nagai, Taku

AU - Nabeshima, Toshitaka

AU - Maurice, Tangui

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