The anti-amnesic effects of sigma1 (σ1) receptor agonists confirmed by in vivo antisense strategy in the mouse

The sigma, (sigma (1)) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma (1) receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma (1) receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[H-3]SKF-10,047 binding to sigma (1) sites showed that B-max values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects: of the selective sigma (1) agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma (1) receptors in memory processes. (C) 2001 Elsevier Science B.V. All rights reserved.