The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax 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 sigma1 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 sigma1 receptors in memory processes.