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Prevention of nimodipine-induced impairment of learning by the selective σ ligand PRE-084

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Summary

The high selectivity of the phencyclidine derivative PRE-084 for sigma (σ) 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 (0.3mg/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 σ antagonist BMY-14802 (10 mg/kg i.p.), implicating the σ sites. These results confirm the beneficial effect of the σ ligand PRE-084 on pharmacological models of learning impairments, and indicate that σ 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.

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Abbreviations

SDL :

step-down latency

EL :

escape latency

VDCC :

voltage-dependent calcium channel

NMDA :

N-methyl-D-aspartate

LTP :

long-term potentiation

DTG :

1,3-di-(2-tolyl) guanidine

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Author notes

  1. T. Maurice

    Present address: Ecole Nationale Supérieure de Chimie, I.N.S.E.R.M. U. 336, Montpellier, France

Authors and Affiliations

  1. Ecole Nationale Supérieure de Chimie, I.N.S.E.R.M. U. 336, Montpellier, France

    A. Privat

  2. National Institute on Drug Abuse, Intramural Research Program, N.I.H., Baltimore, MD

    T. -P. Su

  3. Molecular Simulations, Inc., Sunnyvale, CA, USA

    D. W. Parish

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  4. A. Privat
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Maurice, T., Su, T.P., Parish, D.W. et al. Prevention of nimodipine-induced impairment of learning by the selective σ ligand PRE-084. J. Neural Transmission 102, 1–18 (1995). https://doi.org/10.1007/BF01276561

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  • DOI: https://doi.org/10.1007/BF01276561

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