SA4503, a novel cognitive enhancer with σ1 receptor agonist properties, facilitates NMDA receptor-dependent learning in mice

The selective σ1 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 σ1 receptors. SA4503 also reversed the alternation deficit induced by Nω-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/σ1 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 σ1 receptor ligands were also obtained.