Effects of nociceptin on the exploratory behavior of mice in the hole-board test

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Abstract

The effects of nociceptin on the exploratory behavior of mice were examined using an automatic hole-board apparatus. A low dose of nociceptin (0.01 nmol, i.c.v.) had an anxiolytic effect, as reflected by an increase in head-dipping behavior. However, high doses of nociceptin (1–5 nmol, i.c.v.) produced a dose-dependent anxiogenic effect, as reflected by a decrease in head-dipping behavior. Both the anxiolytic and anxiogenic effects of nociceptin were antagonized by nocistatin, an opioid receptor-like 1 (ORL1) receptor antagonist. Although a low dose (0.01 nmol, i.c.v.) of nociceptin significantly increased the rate of serotonin (5-hyroxytryptamine, 5-HT) turnover in the hippocampus, a high dose (5 nmol, i.c.v.) of nociceptin significantly decreased this turnover in the amygdala. Furthermore, the anxiolytic effect of nociceptin at a low dose was antagonized by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide 3HCl (WAY100635), a 5-HT1A receptor antagonist. On the other hand, the anxiogenic effect of nociceptin at a high dose was antagonized by R(+)-2-dipropylamino-8-hydroxy-1,2,3,4–tetrahydronaphthalene hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist. In conclusion, the results of this study suggest that nociceptin has dose-related anxiolytic and anxiogenic effects as a result of the activation of ORL1 receptors. The present results also suggest that a low dose of nociceptin has an anxiolytic effect via the activation of 5-HT ergic function in the hippocampus, while a high dose of nociceptin has an anxiogenic effect via the inhibition of 5-HT ergic function in the amygdala.

Introduction

Nociceptin/orphanin FQ (nociceptin) was identified as a putative endogenous ligand of an opioid receptor-like 1 (ORL1) receptor that has negligible affinity for μ-. δ-and κ-opioids Mollereau et al., 1994, Nishi et al., 1997. It has been reported that nociceptin induced anxiolytic effects in several animal models of anxiety (light–dark preference, elevated plus maze test, operant conflict) when it was administered intracerebroventricularly (Jenck et al., 1997). Those authors also reported that Ro-64-6198, a selective ORL1 receptor agonist, has dose-dependent anxiolytic-like effects in animal models of anxiety (Jenck et al., 2000). Furthermore, Koster et al. (1999) reported that nociceptin-deficient mice exhibit exaggerated anxious behavior when exposed to a novel environment. These studies indicated that nociceptin plays an important role in regulating the emotional state in rodents. It is also well known that nociceptin influences nociceptive transmission. Interestingly, when nociceptin is administrated intrathecally, it appears to have dual effects consisting of hyperalgesia/allodynia at low doses and clear antinociceptive effects at higher doses Inoue et al., 1999, Sakurada et al., 1999. However, there have been no previous studies on the dose-related effects of nociceptin on the emotional state in rodents.

Serotonin (5-HT) has been widely assumed to be involved in anxiety (Murphy, 1990). In general, new drugs for anxiety are almost all associated with 5-HT neurotransmission. The identification and characterization of multiple 5-HT binding sites in brain tissues and the synthesis of selective ligands for these receptors in the mid-1980s were the starting points for numerous studies on the behavioral effects of 5-HT related drugs in animal models of anxiety. The findings of these studies support the hypothesis that defects in brain 5-HT neuron systems are closely related to anxiety disorders. On the other hand, several investigators have reported that the ORL1 receptor may play an important role in the control of 5-HT ergic neuronal function in the central nervous system Roumy and Zajac, 1999, Siniscalchi et al., 1999, Sbrenna et al., 2000. Siniscalchi et al. (1999) reported that nociceptin inhibited [3H] 5-HT release from rat cerebral cortex slices. Sbrenna et al. (2000) also reported that the ORL1 receptor agonist nociceptin inhibited both spontaneous and K+-evoked [3H] 5-HT efflux. Thus, they suggested that nociceptin may play a role in the presynaptic modulation of 5-HT release. Thus, it is possible that emotional changes produced by nociceptin may alter 5-HT neurotransmission.

The hole-board test, which was first introduced by Boissier and Simon, 1962, Boissier and Simon, 1964 provides a simple method for measuring the response of an animal to an unfamiliar environment. Previously, the hole-board test has been used to assess emotionality, anxiety and/or responses to stress in animals (Rodriguez et al., 1987). Some advantages of this test are that several behaviors can be readily observed and quantified, which makes possible a comprehensive description of the animal's behavior. Several investigators have previously examined the effects of benzodiazepine anxiolytics such as diazepam on behavior in the hole-board test. However, the results from previous investigations are controversial, i.e., exploratory behaviors were either increased Nolan and Parkes, 1973, Crawley, 1985 or decreased (Weischer, 1976). Recently, Takeda et al. (1998) demonstrated using an automatic hole-board apparatus that diazepam and chlordiazepoxide increase head-dipping behavior, while benzodiazepine receptor inverse agonists, such as methyl-β-carboline-3-carboxylate (β-CCM) and N-methyl-β-carboline-3-carboxamide (FG7142), decrease head-dipping behavior. Under these conditions, an anxiolytic state in animals may be reflected by an increase in head-dipping behavior, while an anxiogenic state may be reflected by a decrease in head-dipping behavior.

The primary aim of this study was to examine the effect of nociceptin on emotional properties in mice using the hole-board test. We also investigated the role of 5-HT systems in nociception-induced emotional changes.

Section snippets

Animals

Experiments were conducted with male ICR 6-week-old mice (Tokyo Laboratory Animals Science, Tokyo, Japan), weighing 30–40 g. They had free access to food and water in an animal room that was maintained at 24±1 °C with a 12-h light–dark cycle. This study was carried out in accordance with the Declaration of Helsinki and the guide for the use of laboratory animals of Hoshi University, which is accredited by the Ministry of Education, Science, Sports and Culture.

Behavioral studies

The results in the hole-board test

Effects of nociceptin on exploratory behavior of mice in the hole-board test

Fig. 1 shows the effects of nociceptin on the exploratory behavior of mice in the hole-board test. The lowest dose (0.01 nmol, i.c.v.) of nociceptin significantly increased the counts [F(6, 73)=10.2, P<0.05] and duration of head-dips [F(6, 73)=9.5, P<0.05] and decreased the head-dip latency [F(6, 73)=10.2, P<0.05]. On the other hand, higher doses (0.1–5 nmol, i.c.v.) of nociception dose-dependently reduced the counts and duration of head-dips. Indeed, the highest dose (5 nmol, i.c.v.) of

Discussion

It has been reported that diazepam, a typical benzodiazepine anxiolytic, dose-dependently increased the number and duration of head-dips, whereas the typical anxiogenic drug methyl-βcarboxylate (β-CCM) decreased the number and duration of head-dips and increased the latency to head-dipping Takeda et al., 1998, Kamei et al., 2001. These results strongly suggest that the changes in head-dipping behavior in the hole-board test may reflect the anxiogenic and/or anxiolytic state of animals. In the

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