SA4503, A NOVEL COGNITIVE ENHANCER WITH SIGMA(1) RECEPTOR AGONIST PROPERTIES, FACILITATES NMDA RECEPTOR-DEPENDENT LEARNING IN MICE

The selective sigma(1) receptor agonist 1-(3,4-dimethoxyphenethyl)-4-( 3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to re verse the amnesia induced by the muscarinic receptor antagonist scopol amine at sub-mg/kg doses. We examined its effect on the learning impai rment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alte rnation in the Y-maze for spatial working memory, and step-down type p assive avoidance. SA4503 (0.03-1 mg/kg s.c.) attenuated the dizocilpin e (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped cu rve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating sigma(1) receptors. SA4503 also revers ed the alternation deficit induced by N-w-nitro-L-arginine methyl este r (L-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acte d on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 e ffects in the dizocilpine- and L-NAME-amnesia models, in accordance wi th the purported neurosteroids/sigma(1) receptors interaction. These r esults demonstrate a promising neurobehavioural profile of SA4503, a l igand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on t he potential mechanism of the anti-amnesic effects of sigma(1) recepto r ligands were also obtained.