SA4503, a novel cognitive enhancer with sigma1 receptor agonist properties, facilitates NMDA receptor-dependent learning in mice.
The selective sigma1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to reverse the amnesia induced by the muscarinic receptor antagonist scopolamine at sub-mg/kg doses. We examined its effect on the learning impairment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alternation in the Y-maze for spatial working memory, and step-down type passive avoidance. SA4503 (0.03-1 mg/kg s.c.) attenuated the dizocilpine (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped curve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating sigma1 receptors. SA4503 also reversed the alternation deficit induced by N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acted on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 effects in the dizocilpine- and L-NAME-amnesia models, in accordance with the purported neurosteroids/sigma1 receptors interaction. These results demonstrate a promising neurobehavioural profile of SA4503, a ligand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on the potential mechanism of the anti-amnesic effects of sigma1 receptor ligands were also obtained.
Maurice
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Unité 336 de l'Institut National de la Santé et de la Recherche Médicale, Développement, Plasticité et Vieillissement du Système Nerveux, E.N.S.C.M., Montpellier, France. maurice@cit.enscm.fr
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D000647:Amnesia / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000633:toxicity; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000633:toxicity; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity; D006220:Haloperidol / Q000008:administration & dosage / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011374:Progesterone / Q000008:administration & dosage / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists*; D013037:Spatial Behavior / Q000187:drug effects
D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D009569:Nitric Oxide; D011374:Progesterone; D016291:Dizocilpine Maleate; C101789:SA 4503; D006220:Haloperidol; D019331:NG-Nitroarginine Methyl Ester