Age‐related expression of σ<sub>1</sub> receptors and antidepressant efficacy of a selective agonist in the senescence‐accelerated (SAM) mouse

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<jats:title>Abstract</jats:title><jats:p>The σ<jats:sub>1</jats:sub> receptor is a unique intracellular receptor whose activation results in an efficient modulation of several neurotransmitter responses. Its role as a target for the rapid nongenomic effects of neuro(active)steroids and the age‐related diminutions in steroid levels suggested that targeting the σ<jats:sub>1</jats:sub> receptor might allow alleviation of age‐related neuronal dysfunctions. We examined here the expression and behavioral efficacy of σ<jats:sub>1</jats:sub> receptors in the senescence‐accelerated (SAM) mouse model. The σ<jats:sub>1</jats:sub> receptor mRNA expression was measured by using comparative RT‐PCR in the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum of senescence‐prone SAMP/8 and senescence‐resistant SAMR/1 control animals. No difference was observed between substrains in 6‐, 9‐, and 12‐month‐old (m.o.) mice. The σ<jats:sub>1</jats:sub> protein expression was analyzed by using immunohistochemical techniques. Labeling was intense in the olfactory bulb, hippocampus, hypothalamus, and midbrain of both SAMR/1 and SAMP/8 mice, and the distribution appeared unchanged in 6‐, 9‐, and 12‐m.o. animals. The receptor's in vivo availability was examined by using in vivo [<jats:sup>3</jats:sup>H](+)‐SKF‐10,047 binding. No age‐related difference was observed in the olfactory bulb, hippocampus, hypothalamus, cortex, cerebellum, and brainstem of 6‐ or 12‐m.o. SAMR/1 or SAMP/8 mice. The antidepressant efficacy of the selective agonist igmesine was examined in the forced‐swimming test. The compound decreased significantly the immobility duration at 60 mg/kg in 6‐ and 12‐m.o. SAMR/1 and in 6‐m.o. SAMP/8 mice. In 12‐m.o. SAMP/8 mice, the drug efficacy was facilitated; a significant effect was measured at 30 mg/kg. Decreased neurosteroid levels, particularly of progesterone, were seen in 12‐m.o. SAMP/8 mice that might explain the enhanced efficacy of igmesine. Preserved σ<jats:sub>1</jats:sub> receptor expression and enhanced behavioral efficacy of σ<jats:sub>1</jats:sub> agonists were measured in SAM animals, confirming the therapeutic opportunies for selective ligands against age‐related mood disorders. © 2005 Wiley‐Liss, Inc.</jats:p>

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