σ Receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats

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Abstract

This study examined the effects of the σ receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither σ receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a σ1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-monohydrochloride. These results suggest that the interaction of σ1 receptors with NMDA receptors modulates spatial memory in rats.

Introduction

The σ receptors in the central nervous system were originally proposed by Martin et al. (1976)to be the binding sites for (±)-N-allylnormetazocine ((±)-SKF10,047). The σ receptor ligand (+)-SKF10,047 and phencyclidine were thought to act through a single binding site termed the σ-phencyclidine receptor. It is now clear that two distinct binding sites exist with different populations throughout the brain, a high-affinity site for (+)-SKF10,047, σ receptors, and a low-affinity site for (+)-SKF10,047, which corresponds to a phencyclidine binding site (Largent et al., 1986; Manallack et al., 1986; Quirion et al., 1987; Walker et al., 1990). It is well accepted that σ sites represent two different classes of binding sites: σ1 sites, which have high affinity and stereoselectivity for (+)-SKF10,047 and (+)-pentazocine; and σ2 sites, which have a lower affinity and no stereoselectivity (Quirion et al., 1992). 1-(3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) is a novel and selective σ1 receptor agonist (Matsuno et al., 1996, Matsuno et al., 1997; Senda et al., 1996). Recently, σ (σ1) receptors have been purified and cloned. The deduced amino acid sequence shared homology with that of fungal proteins involved in sterol synthesis (Hanner et al., 1996).

The phencyclidine binding site is located inside the ion channel associated with the NMDA receptor complex, and the ligands for the phencyclidine binding site are known to act as non-competitive NMDA receptor antagonists (Wong et al., 1986; Wong et al., 1988; Lodge and Johnson, 1990). There are many reports showing that ligands for the phencyclidine binding site, including the more selective derivative dizocilpine, significantly impair learning and memory in rodents and monkeys by blocking NMDA receptor-mediated glutamatergic neurotransmission (Butelman, 1989; Tan et al., 1989; Ward et al., 1990; Boyce et al., 1991; Pontecorvo et al., 1991; Ogura and Aigner, 1993). We have recently suggested that impairment of spatial memory in mice caused by dizocilpine is due to disruption of NMDA/nitric oxide/cyclic GMP signaling (Yamada et al., 1996a, Yamada et al., 1996b). Although the function of σ receptors is not fully understood, some σ receptor ligands have been demonstrated to facilitate the NMDA response in the hippocampus (Monnet et al., 1990, Monnet et al., 1992). It has been demonstrated that in both short-term and long-term memory tests, σ receptor ligands, such as 1,3-di(2-tolyl)-guanidine (DTG), (+)-SKF10,047, (+)-pentazocine, and SA4503, markedly prevent the amnesia induced by dizocilpine (Maurice et al., 1994a, Maurice et al., 1994b; Maurice and Privat, 1997). Furthermore, intrahippocampal administration of (+)-SKF10,047 has been shown to attenuate the working memory impairment induced by concurrent intrahippocampal administration of dizocilpine in a three-panel runway task (Ohno and Watanabe, 1995). These behavioral studies support the potentiating effect of σ receptor ligands on NMDA receptor-mediated neurotransmission, as demonstrated electrophysiologically (Monnet et al., 1990, Monnet et al., 1992), and suggest that this interaction plays a role in NMDA-dependent learning and memory processes (Maurice and Lockhart, 1997). In this study, therefore, we examined the effects of σ receptor ligands (+)-SKF10,047 and SA4503 on the dizocilpine-induced impairment of spatial memory in a radial arm maze task in rats.

Section snippets

Materials

The rats used in the present study were males of the Wistar strain (20 weeks old; Charles River Japan, Yokohama, Japan) weighing 250±20 g at the beginning of experiments. All animals were kept in a regulated environment (23±0.5°; 50±0.5% humidity) with a 12-h light/dark cycle (light on 9:00 a.m. and 9:00 p.m.) and had free access to food and water. Dizocilpine and (+)-SKF10,047 were purchased from Research Biochemicals International (Natick, MA, USA). SA4503 and N,N

Effect of dizocilpine on performance in the radial arm maze task

Fig. 1 shows the effect of dizocilpine, in the dose range of 0.05–0.2 mg/kg, on the performance in the radial arm maze task in rats. A one-way ANOVA with repeated measures revealed a significant effect of group (F(3,43)=9.596, P<0.0001). Post-hoc analysis using the Bonferroni test revealed that dizocilpine at a dose of 0.2 mg/kg significantly increased the number of errors (Fig. 1A). When the errors were subdivided into the working memory and reference memory categories, a significant group

Discussion

In the present study, we found that systemic administration of dizocilpine impaired significantly both working and reference memory, as assessed by the radial arm maze task. These results suggest that NMDA receptor-mediated glutamatergic neurotransmission plays an important role not only in working memory, but also in reference memory. It has been shown that intrahippocampal injections of NMDA receptor antagonists, such as cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS19755) and

Acknowledgements

We are grateful to Santen Pharmaceutical (Osaka, Japan) and Taisho Pharmaceutical (Tokyo, Japan) for the generous donation of SA4503 and NE-100, respectively. This study was supported, in part, by a Grant-in-Aid for Science Research from the Ministry of Education, Science, and Culture of Japan (Nos. 08457027 and 10044260).

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