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

The σ 1 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 1 receptor might allow alleviation of age‐related neuronal dysfunctions. We examined here the expression and behavioral efficacy of σ 1 receptors in the senescence‐accelerated (SAM) mouse model. The σ 1 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 1 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 [ 3 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 1 receptor expression and enhanced behavioral efficacy of σ 1 agonists were measured in SAM animals, confirming the therapeutic opportunies for selective ligands against age‐related mood disorders. © 2005 Wiley‐Liss, Inc.