MK-801-induced hyperlocomotion: Differential effects of M100907, SDZ PSD 958 and raclopride

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Abstract

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-d-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-α(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine-methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (−)-[4aR,10aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl-benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to  ̃10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([((−)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition.The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.

Introduction

Several recent hypotheses on the pathophysiology of schizophrenia (Kim et al., 1980; Kornhuber and Kornhuber, 1986; Javitt, 1987; Carlsson, 1988) include a suggestion that deficient central glutamatergic transmission is an important factor. In animals, experimental impairment of glutamatergic transmission can be produced by pharmacological intervention at the level of the NMDA receptor. The most potent and selective antagonist known to interact in an un-competitive manner with this receptor complex, is [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine; Wong et al., 1986; Javitt and Zukin, 1991). In rodents, MK-801 induces a behavioral syndrome, including hyperlocomotion, head weaving, body rolling, ataxia, reduced rearing behavior and stereotypies (Clineschmidt et al., 1982; Tricklebank et al., 1989; Liljequist et al., 1991), which has been proposed to represent an animal model of certain aspects of schizophrenia (Carlsson and Carlsson, 1990; Tiedtke et al., 1990).

Dopamine D2 receptor antagonists given systemically inhibit the MK-801-induced hyperlocomotion (Clineschmidt et al., 1982; Hoffman, 1992; Ögren and Goldstein, 1994), and likewise, the dopamine D1 receptor antagonist SCH 23390 (Iorio et al., 1983) reduces locomotion induced by MK-801 (Ouagazzal et al., 1993). None of these studies reported how the dopamine D1 or D2 receptor antagonists affected vehicle-treated (non-MK-801) animals. However, Dall'Olio et al. (1992) described a 50% reduction in MK-801-induced hypermotility, using either SCH 23390 or the dopamine D2 receptor antagonist YM 09151-2 in doses that left locomotion in saline-treated animals unaffected. Furthermore, we have found that, given in doses that were equally efficient with regard to inhibition of motor activity in saline-treated controls, SCH 23390 had a greater inhibitory effect on MK-801-induced hyperactivity than did the dopamine D2 receptor antagonist raclopride (Martin et al., 1994).

Since SCH 23390 also has considerable affinity for 5-hydroxytryptamine (5-HT)2 receptors in vitro and in vivo (Christensen et al., 1984; Bischoff et al., 1986; Riddall, 1992), a novel selective dopamine D1 receptor antagonist (400 fold less active at dopamine D2 receptors), (−)-[4aR,10aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl-benzo[g]quinoxaline-6-ol (SDZ PSD 958; Markstein et al., 1996) was used in the present study. In an attempt to evaluate to what extent the marked effect of SCH 23390 on MK-801-induced hyperactivity can be attributed to antagonism at each of, or an interaction between, these receptors, SDZ PSD 958 and R(+)-α(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine-methanol (MDL100,907; M100907), a highly selective 5-HT2A receptor antagonist, were employed. Also, the importance of dopamine D2 receptors was assessed using ((−)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate) (raclopride; Köhler et al., 1985) as selective tool. Dose–response relationships were evaluated for each drug on MK-801-treated and vehicle-treated animals. Furthermore, to evaluate the interaction between SDZ PSD 958 and M100907, both drugs were administered concomitantly in various doses according to an orthogonal matrix experimental design.

Section snippets

Animals

Male albino mice (n=242) of the NMRI strain weighing 18–20 g were purchased from BeeKay, Sollentuna. The experimental procedures were approved by the Animal Ethics Committee of the University of Göteborg.

Drugs

MK-801 was obtained from Research Biochemicals, MA. M100907 was generously supplied by the Marion Merrell Dow Research Institute, Cincinnati. Raclopride tartrate and SDZ PSD 958 were kindly provided by Professor Ahlenius at Astra Läkemedel AB and Dr. Markstein, Sandoz Pharma, Basel,

Effects of SDZ PSD 958 and M100907 on spontaneous locomotion in mice

The dose-dependent effects of SDZ PSD 958 (0.01–8 mg/kg s.c.), are shown in Fig. 1. The two-factor ANOVA revealed an overall statistical significant difference between treatment groups (F(7,37)=14.26; P<0.0001) and a main significant effect of time (F(5,185)=77.28; P<0.0001). There was also a significant interaction between dose and time (F(35,185)=1.802; P<0.0001). Fischer's PLSD test indicated that animals treated with doses of 0.1 mg/kg, or higher, of SDZ PSD 958 showed a statistically

Effects of M100907

The main finding of this study was that low doses of the selective 5-HT2A receptor antagonist M100907 were highly effective in counteracting the hyperlocomotion elicited by the un-competitive NMDA receptor antagonist MK-801. A dose of 0.1 mg/kg M100907 totally abolished the MK-801-induced hyperlocomotion, while it had no significant effect on locomotion in saline-treated mice (Fig. 5b). No apparent increase in the ataxia present in MK-801-treated mice was seen after addition of M100907.

The

Acknowledgements

This study has been supported by grants from the Swedish Medical Research Council (No. 155 and 9067), the Marion Merrell Dow Research Institute, Strasbourg, Kerstin och Bo Pfannenstills stifelse, Lundbeckfonden, Wilhelm och Martina Lundgrens vetenskapsfond, Göteborgs Kungliga Vitterhets- och Vetenskapssamhälle and Åhlénstiftelsen. The generous gifts of compounds from companies mentioned in Section 2are gratefully acknowledged. The excellent technical assistance of Malin Lundgren, Marie Nilsson

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