The potentiating effect of low doses of σ ligands on the N-methyl-d-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the σ ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (-)-isomers, significantly decreased MK-801 (100 μg/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 μg/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative σ antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 μg/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the σ ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1-1000 μg/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of σ ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.
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