The anti-amnesic effects of sigma1 (sigma1) receptor agonists confirmed by in vivo antisense strategy in the mouse.
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.
Maurice
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INSERM U. 336, Behavioral Neuropharmacology group, Institut de Biologie, 4, boulevard Henri IV, 34060, Montpellier, France. maurice@medecine.univ-montp1.fr
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D000647:Amnesia / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate; D018690:Excitatory Amino Acid Agonists; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use; D018697:Nootropic Agents / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists*
D018690:Excitatory Amino Acid Agonists; D009025:Morpholines; D018697:Nootropic Agents; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D017480:Receptors, sigma; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D016291:Dizocilpine Maleate; C012134:SK&F 10047; C101789:SA 4503; D010620:Phenazocine