Prevention of nimodipine-induced impairment of learning by the selective sigma ligand PRE-084.
The high selectivity of the phencyclidine derivative PRE-084 for sigma (sigma) sites is demonstrated. We previously reported that this compound is able to markedly attenuate the impairment of learning induced in mice by the non-competitive NMDA antagonist MK-801, and the cholinergic nicotinic antagonist mecamylamine. In this study, we examined the effect of PRE-084 on the impairment of learning induced by acute administration of the calcium channel antagonist nimodipine. Nimodipine (0.3 mg/kg i.p.) impaired the spontaneous alternation behaviour in a Y-maze, decreased the step-down latency (SDL) in a passive avoidance task, and altered place learning and retention in a water-maze paradigm, with no marked effect on the motility observed using an open-field test. Preadministration of PRE-084 resulted in an attenuation of the impairment of alternation, in the 0.3-1 mg/kg s.c. range, in a marked increase in SDL, at 1-3 mg/kg, and improved place learning and retention in the water-maze, at 1 mg/kg. The effects on alternation behaviour and passive avoidance were completely prevented by co-administration of the purported sigma antagonist BMY-14802 (10 mg/kg i.p.), implicating the sigma sites. These results confirm the beneficial effect of the sigma ligand PRE-084 on pharmacological models of learning impairments, and indicate that sigma sites may modulate Ca2+ fluxes through VDCC, which may in turn bear some as yet unknown relationship to the previously described interaction with neurotransmitter systems.
Maurice
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I.N.S.E.R.M. U. 336, Montpellier, France.
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Parish
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Privat
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D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D014828:Vocalization, Animal / Q000187:drug effects
D009025:Morpholines; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D009553:Nimodipine