The anti-amnesic effects of sigma(1) (sigma(1)) 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 oli godeoxynucleotide (aODN) targeting the sigma (1) receptor mRNA and a mismat ched analog (mODN) were administered intracerebroventricularly for 3 days i n 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 hip pocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum of aODN tr eated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippo campus and cortex but not in the cerebellum. The anti-amnesic effects: of t he selective sigma (1) agonists PRE-084 or SA4503 were evaluated against th e learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The ant i-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-trea tment, were blocked after aODN administration. These observations bring a m olecular basis to the modulatory role of sigma (1) receptors in memory proc esses. (C) 2001 Elsevier Science B.V. All rights reserved.