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

Abstract

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.

The antidepressant-like effect induced by the sigma1 (σ1) receptor agonist igmesine involves modulation of intracellular calcium mobilization

“…On the plasma membrane, the s 1 receptor interacts and modulates the activity of VDCC, as observed in previous studies (Brent et al 1997;Hayashi et al 2000). In terms of behavioral consequences, it was previously observed that selective s 1 receptor agonists could attenuate the learning impairments induced in mice by acute systemic administration of nimodipine (Maurice et al 1995). The present study also brings a pertinent example of the interaction of s 1 receptor with VDCC activation, showing that both L-type and N-type VDCC are involved in the s 1 receptormediated antidepressant-like effect in mice.…”

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

“…In healthy animals, nimodipine may impair learning (Maurice et al 1995). However, nootropic effects of nimodipine have been previously demonstrated in other neuropsychiatric disorders (Pantoni et al 1996;Sze et al 1998), aged animals (Levere andWalker 1992;Sandin et al 1990) and animals with anticholinergic impairments in learning (Balakrishnan and Pandhi 1997).…”

Understanding the Molecular Mechanism of Sigma-1 Receptors: Towards A Hypothesis that Sigma-1 Receptors are Intracellular Amplifiers for Signal Transduction

“…These included impairment elicited either by chemically treating the animals respectively with the nicotinic acetycholine receptor blocker mecamylamine [29], the calcium channel blocker nimodipine [30], and the β-amyloid 25-35 aggregate [31], or the model of genetically produced senescenceaccelerated mice [32]. The surprise was that the sigma-1 receptor agonists are active in improving the mnemonic deficit elicited by all the above treatment procedures.…”