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Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system
Neuropharmacology 61 (2011) 228e233
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system Tomotaka Murotani a, *, Tomoko Ishizuka b, Yuka Isogawa a, Michitaka Karashima a, Atsushi Yamatodani a a b
Department of Medical Science and Technology, Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan Department of Pharmacology, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 February 2011 Received in revised form 1 April 2011 Accepted 7 April 2011
The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5 mg/kg, i.p.) or aripiprazole (1 mg/kg, i.p.), which have binding affinities to 5-HT1A, 2A, 2B and 2C receptors decreased food intake in C57BL/6 N mice with concomitant increase of hypothalamic histamine release. However, a selective D2-antagonist, haloperidol (0.5 mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H1 receptordeficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT2A-antagonists, volinanserin (0.5, 1 mg/kg, i.p.) and ketanserin (5, 10 mg/kg, i.p.), significantly increased histamine release and 5-HT2B/2C -antagonist, SB206553 (2.5, 5 mg/kg, i.p.), slightly increased it. On the contrary, 5-HT1A -selective antagonist, WAY100635 (1, 2 mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT2 receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT2 receptors resulting in anorexia via the H1 receptor. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Histamine H1 receptor 5-HT receptor Anorexia Schizophrenia Antischizophrenic drugs
1. Introduction The central histaminergic system has been shown to be involved in the regulation of various physiological functions including feeding behavior (Morimoto et al., 2001; Wada et al., 1991). The intracerebroventricular injection of histamine (Itowi et al., 1988; Lecklin et al., 1998) or the peripheral injection of L-histidine, the precursor of histamine (Orthen-Gambill, 1988; Sheiner et al., 1985; Vaziri et al., 1997; Yoshimatsu et al., 2002) decreased food intake, while depletion of neuronal histamine by a-fluoromethylhistidine, a specific inhibitor of histamine-forming enzyme, increased food intake (Morimoto et al., 1999; Orthen-Gambill and Salomon, 1992).
Abbreviations: 5-HT, serotonin; DOI, 2,5-dimethoxy-4-iodoamphetamine; H1RKO, H1 receptor-knock out mice; HPLC, high-performance liquid chromatography; WT, wild type; ANOVA, analysis of variance. * Corresponding author. Present address: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Kobe, Hyogo 650-0017, Japan. Tel.: þ81 78 382 6287; fax: þ81 78 382 2562. E-mail address: [email protected] (T. Murotani). 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.04.003
Furthermore, we recently reported that the peripheral injection of clobenpropit, an H3-antagonist, which increases histamine release in the brain, decreases food intake (Ishizuka et al., 2008). Lecklin et al. (1998) reported that histamine- and a selective H1-agonistinduced decrease in food intake were inhibited by an H1-antagonist but not by an H2-antagonist. These findings suggest that neuronal histamine suppresses food intake via the H1 receptor. Several studies indicate the possibility that histaminergic tone is modulated by serotonin (5-HT). For example, 5-HT excites the neurons of the tuberomammillary nucleus, which contain the origin of histaminergic neurons, by activation of the Naþ/Ca2þexchange (Eriksson et al., 2001, 2002; Sergeeva et al., 2003). The 5HT receptor agonist decreased the metabolic turnover of histamine and this effect is reversed by 5-HT antagonists (Oishi et al., 1992). Chemical lesioning of the 5-HT system in the neonatal period results in the reduction of histamine concentrations in the brains of adult rats. (Josko et al., 2010). Moreover, Morisset et al. (1999) reported that atypical antipsychotics, which antagonize some 5-HT receptor subtypes, increased histamine turnover in the brain. The effect was not
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shared by conventional antipsychotics like haloperidol which have no effect on 5-HT receptors, and was reversed by a 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). These findings imply the interaction of serotonin with the histaminergic system. Modulation of feeding behavior associated with the use of atypical antipsychotics has also been reported. Ota et al. (2002) reported that administration of a relatively high dose of risperidone (0.5 mg/kg) reduces food intake leading to weight loss in rats, while a low dose of risperidone (0.005 and 0.05 mg/kg) increases food intake and enhances weight gain. In clinical reports, aripiprazole reduced body weight in schizophrenic patients (Madhusoodanan et al., 2004) and in patients who became obese during corticosteroid treatment (Terao, 2008). In the present study, we investigated the effects of a single administration of antipsychotics on food intake and on the central histamine release in mice by in vivo microdialysis. Furthermore, to clarify which subtypes of 5-HT receptors are involved in regulating histaminergic tone following antipsychotic administration, the effect of selective 5-HT-antagonists on histamine release was examined.
Histamine contents in the brain after atypical antipsychotics injection were determined during the light phase. One hour after drug injection (risperidone: 0.5 mg/kg, i.p.; aripiprazole: 1 mg/kg, i.p.; solvent, i.p.), mice were sacrificed by decapitation and then the decapitated heads were dropped directly into ice-cold water for one second to prevent neurotransmitter decay. Brains were removed from the calvarium and placed on a chilled aluminum block. The brain was dissected into ten regions (olfactory bulb; prefrontal cortex; cortex; striatum; hippocampus; thalamus; hypothalamus; midbrain; brain-stem; cerebellum) according to the Glowinski and Iversen method (Glowinski and Iversen, 1966) with a slight modification (Murotani et al., 2007). Each section of brain tissue was put into a sampling tube and 9 volumes of 2% perchloric acid solution including 1 mM EDTA-Na2 and 1 mM Na2S2O5 was added to the tube. The tissue was then homogenized with a sonicator for 5e10 s and centrifuged (10,000 g 30 min). The concentration of histamine in the supernatant was determined using the HPLC-fluorometric method described above.
2. Materials and methods
2.5. The involvement of 5-HT receptors in histamine release
2.1. Animals
The possible involvement of the serotonergic system in the antipsychoticinduced histamine release was examined in WT mice using in vivo microdialysis after i.p. injections of the following 5-HT-receptor antagonists; WAY-100635 (a selective 5-HT1A antagonist, 1 mg/kg: n ¼ 6, 2 mg/kg: n ¼ 4, SigmaeAldrich Japan, Tokyo, Japan), volinanserin (a 5-HT2A antagonist, 0.5 mg/kg: n ¼ 4, 1 mg/kg: n ¼ 5, Toronto Research Chemicals Inc., Ontario, Canada) and ketanserin (a 5-HT2A antagonist, 5 mg/kg: n ¼ 5, 10 mg/kg: n ¼ 7, SigmaeAldrich Japan, Tokyo, Japan), and SB 206553 (a 5-HT2B,2C antagonist, 2.5 mg/kg: n ¼ 4, 5 mg/kg: n ¼ 5,Tocris Bioscience, Bristol, UK).
Eight-week-old male C57BL/6N mice (wild type: WT, Japan SLC, Shizuoka, Japan) and H1 receptor-knock out mice (H1R-KO, Inoue et al., 1996) were used. Animals were kept in cages on a 12/12 h light/dark schedule (lights on, 08:00 h to 20:00 h) and maintained at 25 1 C with 50 10% humidity. All animals had free access to standard pelleted chow (MF, Oriental Yeast, Osaka, Japan) and tap water and experiments were performed in accordance with the guidelines of the Animal Care Committee of the Graduate School for Medicine, Osaka University. Maximum effort was made to minimize the number of animals used and to limit any suffering. 2.2. Behavioral experiment The behavioral experiment was performed as described previously (Morimoto et al., 1999) with a slight modification. One week before the experiment, mice were transferred to individual glass-metabolic cages (Metabolica-MM, Sugiyama-Gen Iriki, Tokyo, Japan). During the training period, the eating time of mice was limited to 3 h after the onset of the dark phase. The amount of food intake was measured every day, and the average daily amount for 3 days before the experimental day was calculated after the daily food intake had stabilized. Following the training period, mice were intraperitoneally injected with risperidone (0.5 mg/kg, n ¼ 4), aripiprazole (1 mg/kg, n ¼ 4) and haloperidol (0.5 mg/kg, n ¼ 6) just before the onset of the dark phase. All drugs were suspended in saline containing 0.1% carboxymethyl cellulose and the same volume of solvent was injected into the control group (n ¼ 5). The ratio of food intake after drug injection to average intake was calculated. The behavioral experiment was also conducted in H1R-KO mice to examine the involvement of H1 receptor in atypical antipsychotic-induced anorexia.
was placed incorrectly were excluded from analysis. The released extracellular histamine levels in dialysate fractions were determined by high-performance liquid chromatography (HPLC) using the fluorometric method (Yamatodani et al., 1985) with slight modifications (Mochizuki et al., 1991). In each microdialysis experiment, the fractions following drug administration were expressed as a percentage of the mean of the baseline release level. 2.4. Brain histamine contents
2.6. Statistical analysis Data are presented as means and S.E.M. As for food intake and histamine contents, the significance of differences between genotypes was analyzed by oneway analysis of variance (ANOVA). When significant main effects were found, the data were further analyzed by the post-hoc least significant difference test. For the microdialysis study, significance of differences between the basal release and subsequent fractions in each group was analyzed by one-way analysis ANOVA for repeated measures. When significant main effects were found, the data were further analyzed by the post-hoc least significant difference test. A p value < 0.05 was considered significant.
2.3. In vivo microdialysis In vivo microdialysis procedures were carried out during the light phase. Overnight-fasted mice were anesthetized with urethane (1.2 g/kg, i.p.) and placed in a stereotaxic apparatus (Kopf Instrument, Tujunga, CA, USA). A microdialysis probe (MAB6; membrane length: 1 mm; ALS/Microbiotech, Stockholm, Sweden) aimed at the anterior hypothalamus was inserted using the following coordinates: AP: 0.7; LM: 0.4; DV: 5.4 mm relative to the bregma and skull surface, according to the atlas of Paxinos and Franklin (2001). The probe was perfused with artificial cerebrospinal fluid (Mochizuki et al., 1991) at a rate of 0.8 mL/min. Following 100 min perfusion to stabilize the neurotransmitter release, dialysates were collected every 25 min. After the first three baseline samples had been collected, mice received i.p. injection of the respective drugs; risperidone (0.5 mg/kg: n ¼ 6, 1 mg/kg, n ¼ 5, RisperdalÒ, Janssen Pharmaceutical, Tokyo, Japan), aripiprazole (1 mg/kg: n ¼ 7, 2 mg/kg: n ¼ 4, AbilifyÒ, Otsuka Pharmaceutical, Tokyo, Japan), haloperidol (0.5 mg/ kg: n ¼ 5, 1 mg/kg: n ¼ 7, Wako Pure Chemical, Osaka, Japan). The same volume of solvent was injected to the control group (n ¼ 5). Samples were collected for 175 min after the drug injection. After the microdialysis experiment, the probe was removed and the mice were perfused with 0.9% (wt/vol) saline through the left ventricle followed by 10% (vol/vol) formalin. The brains of the mice were examined for histological verification of the placement of the probe. Animals in which the probe
Fig. 1. Food intake after drug injection in WT mice (The ratio of food intake after drug injection to average intake). Risperidone (0.5 mg/kg, i.p., n ¼ 4) and aripiprazole (1 mg/ kg, i.p., n ¼ 4) significantly decreased food intake (risperidone: 68.7 9.5 %, aripiprazole: 72.7 6.8 %, p < 0.05) compared to that of the control group (99.7 2.4%, n ¼ 5). Haloperidol (0.5 mg/kg, i.p., n ¼ 6) did not change food intake (90.6 6.7%). Symbols used: ( ) risperidone; ( ) aripiprazole; (-) haloperidol; (,) control. *p < 0.05.
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histamine release (0.5 mg/kg, i.p., F(9,36) ¼ 0.78, p ¼ 0.63, n ¼ 5; 1 mg/kg, i.p., F(9,54) ¼ 1.26, p ¼ 0.28, n ¼ 7; Fig. 2c).
3. Results 3.1. Behavioral experiments in WT mice
3.3. Brain histamine concentrations In WT mice, risperidone (0.5 mg/kg, i.p.) significantly decreased the amount of food intake within 3 hours (68.7 9.5%, n ¼ 4, p < 0.05, Fig. 1) and aripiprazole (1 mg/kg, i.p.) also significantly decreased food intake (72.7 6.8%, n ¼ 4, p < 0.05, Fig. 1) compared to that in the control group (99.7 2.4%, n ¼ 5, Fig. 1). There was no significant change in the haloperidol (0.5 mg/kg, i.p.)-injected group (90.6 6.7%, n ¼ 6, Fig. 1). 3.2. In vivo microdialysis studies in WT mice I.p. injection of risperidone immediately increased histamine release in the anterior hypothalamus of WT mice, and high levels were maintained for about 3 h (0.5 mg/kg, i.p., F(9,45) ¼ 3.22, p < 0.01, n ¼ 6; 1 mg/kg, i.p., F(9.36) ¼ 17.3, p < 0.01, n ¼ 5; Fig. 2a). Similarly, the injection of aripiprazole significantly increased histamine release (1 mg/kg, i.p., F(9,54) ¼ 3.42, p < 0.01, n ¼ 7; 2 mg/kg, i.p., F(9,27) ¼ 6.51, p < 0.01, n ¼ 4; Fig. 2b), but the percentage of increase compared to basal release was lower than that induced by risperidone. Haloperidol had no effect on
a
Risperidone (0.5 mg/kg, i.p.) and aripiprazole (1 mg/kg, i.p.) injected at the same dose that increased histamine release on microdialysis study did not change the histamine concentration in the brain compared to that in the control (Table 1). 3.4. Behavioral experiments in H1R-KO mice In H1R-KO mice, there were no significant differences in food intake among the risperidone group (0.5 mg/kg, i.p.), aripiprazole group (1 mg/kg, i.p.) and control group (risperidone: 98.3 10.8%, n ¼ 4; aripiprazole: 96.3 10.5%, n ¼ 4, control: 108.6 12.0%, n ¼ 4, Fig. 3) (F(2,9) ¼ 1.40, p ¼ 0.30, Fig. 3). 3.5. In vivo microdialysis studies in H1R-KO mice I.p. injection of risperidone increased histamine release in the anterior hypothalamus of H1R-KO mice (0.5 mg/kg, i.p., F(9,18) ¼ 4.53, p < 0.01, n ¼ 3; 1 mg/kg, i.p., F(9,27) ¼ 7.97, p < 0.01, n ¼ 4,
b
c
Fig. 2. Histamine release in the WT mouse hypothalamus after injection of (a) risperidone (0.5 mg/kg, n ¼ 6 (Δ); 1 mg/kg, n ¼ 5 (,), i.p.), (b) aripiprazole (1 mg/kg, n ¼ 7 (Δ); 2 mg/ kg, n ¼ 4 (,), i.p.) and (c) haloperidol (0.5 mg/kg, n ¼ 5 (Δ); 1 mg/kg, n ¼ 7 (,), i.p.). The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
T. Murotani et al. / Neuropharmacology 61 (2011) 228e233 Table 1 Histamine concentrations in the brain after atypical antipsychotic injection.
Olfactory bulb Prefrontal cortex Cortex Striatum Hippocampus Thalamus Hypothalamus Midbrain Brainstem Cerebellum
Control
Risperidone (0.5 mg/kg)
Aripiprazole (1 mg/kg)
n ¼ 4w5
n ¼ 6w7
n ¼ 3w4
190.2 25.6 236.1 12.6 150.8 22.7 187.1 11.8 91.1 9.8 303.0 20.4 694.6 85.9 330.3 49.3 61.2 6.6 168.9 39.1
211.8 28.9 241.7 29.0 150.1 9.0 195.1 6.9 81.6 5.6 294.6 72.9 590.1 56.6 245.0 23.4 73.0 7.6 163.1 11.8
184.9 25.6 255.5 15.0 178.2 3.4 210.1 24.9 104.8 24.6 298.6 34.2 682.9 182.6 295.1 82.6 66.6 14.3 178.0 29.1
All data are presented as means S.E.M. (pmol/g).
Fig. 4a). The injection of aripiprazole significantly increased histamine release (1 mg/kg, i.p., F(9,63) ¼ 2.85, p < 0.01, n ¼ 8; 2 mg/kg, i.p., F(9,45) ¼ 3.69, p < 0.01, n ¼ 6, Fig. 4b) although the effect was not as remarkable as that of risperidone. 3.6. The involvement of 5-HT receptors in histamine release I.p. injection of volinanserin significantly increased histamine release in the anterior hypothalamus of WT mice (0.5 mg/kg, F(9,27) ¼ 12.2, p < 0.01, n ¼ 4; 1 mg/kg, F(9,36) ¼ 5.23, p < 0.01, n ¼ 5; Fig. 5a), and the injection of ketanserin also increased histamine release (5 mg/kg, F(9,36) ¼ 2.94, p < 0.05, n ¼ 5; 10 mg/ kg, F(9,54) ¼ 2.64, p < 0.05, n ¼ 7; Fig. 5b). SB 206553 significantly increased histamine release (2.5 mg/kg, i.p., F(9,36) ¼ 4.18, p < 0.01, n ¼ 4; 5 mg/kg, F(9,36) ¼ 3.18, p < 0.01, n ¼ 5; Fig. 5c), although the percentage of increase was small. Contrarily, i.p. injection of WAY100635 had no effect on histamine release (1 mg/kg, F(9,45) ¼ 1.15, p ¼ 0.35, n ¼ 6; 2 mg/kg, F(9,27) ¼ 0.98, p ¼ 0.48, n ¼ 4; Fig. 5d). 4. Discussion In the present study, food intake was decreased by administration of atypical antipsychotics, risperidone (0.5 mg/kg) and aripiprazole
Fig. 3. Food intake after drug injection in H1R-KO mice (The ratio of food intake after drug injection to average intake). ANOVA did not demonstrate a significant main effect of atypical antipsychotics on food intake (F(2,9) ¼ 1.40, p ¼ 0.30). Symbols used: ( ) risperidone (0.5 mg/kg, 98.3 10.8%, n ¼ 4); ( ) aripiprazole (1 mg/kg, 96.3 10.5%, n ¼ 4); (,) control (108.6 12.0%, n ¼ 4).
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(1 mg/kg) in WT mice (Fig. 1). These findings are partially consistent with the previous study that chronic administration of a relatively high dose of risperidone (0.5 mg/kg, 2weeks) gradually decreased food intake in rats but a low dose did not (0.005, 0.05 mg/kg) (Ota et al., 2002). Histamine release in the hypothalamus was significantly increased by the administration of risperidone (0.5, 1 mg/kg, Fig. 2a) and aripiprazole (1, 2 mg/kg, Fig. 2b) in WT mice. On the contrary, haloperidol (0.5, 1 mg/kg) did not modulate histamine release (Fig. 2c), which agrees with the findings of a previous report indicating that atypical antipsychotics including risperidone increased metabolic turnover of histamine in the brain (Morisset et al., 1999), and that the histaminergic tone was not changed by haloperidol even at higher doses (5, 10 mg/kg) (Ito et al., 1997). The present findings demonstrate that risperidone and aripiprazole at the dose used increased hypothalamic histaminergic activity without modulating the histamine concentration (Table 1), which reflects histamine synthesis or metabolism in the brain. In contrast to the findings in WT mice, the same dose of risperidone and aripiprazole did not induce anorexia in H1R-KO mice (Fig. 3) although increased histamine release induced by these antipsychotics was observed (Fig. 4a and b). Central histamine suppresses feeding behavior via the H1 receptor (Morimoto et al., 2001) and H1RKO mice showed a normal increase in histamine release after risperidone and aripiprazole injection in the present study. Thus, hypothalamic histamine release responds to atypical antipsychotics in H1R-KO mice; however, these animals do not develop drug-related anorexia because they are devoid of H1 receptors. Selective 5-HT2A antagonists, volinanserin (0.5, 1 mg/kg, Fig. 5a) and ketanserin (5, 10 mg/kg, Fig. 5b), and the 5-HT2B, 2C antagonist, SB206553 (2.5, 5 mg/kg, Fig. 5c) significantly increased the histamine release. However, the selective 5-HT1A antagonist, WAY-100635 (1, 2 mg/kg, Fig. 5d), did not have any effects on histamine release. These findings indicate that the release of central histamine was modulated by 5-HTergic transmission via 5-HT2A and 5-HT2B, 2C receptors but not via 5-HT1A receptor. Between these three receptors, the 5-HT2A receptor may be the more likely candidate to regulate histamine release based on a comparison of the efficacy of antagonists (Fig. 5a and b vs. Fig. 5c). Previous reports demonstrated that risperidone has a higher affinity to 5-HT2 receptor subtypes than to 5-HT1A receptor in contrast to aripiprazole, which has a higher affinity to the 5-HT1A receptor (Kroeze et al., 2003; Hirose and Kikuchi, 2005). These differences in binding affinity to 5-HT receptor subtypes between risperidone and aripiprazole might have contributed to differences in the efficacy in releasing histamine in the present study. Morisset et al. (1999) reported that atypical antipsychotics including clozapine, olanzapine, risperidone, thioridazine, seroquel and iloperiodone increased metabolic turnover of histamine in the brain. The effect was not shared by haloperidol, sulpiride, raclopride and remoxipride, and was reversed by a 5-HT2A receptor agonist, DOI. Based on these findings, they concluded that atypical antipsychotics stimulate histamine neuronal activity via blockade of the 5-HT2A receptor, which is consistent with the present findings. 5-HT have direct or indirect influence on feeding behavior. The fact that patient with anorexia nervosa have abnormality in their expression of 5-HT receptor (Asarian and Langhans, 2010) is good example which suggests a certain connection between 5-HT and appetite. Thus, further study to clarify the effects of 5-HT2 antagonists themselves on food intake is needed. Risperidone and aripiprazole have less potential to cause druginduced weight gain than olanzapine and clozapine (Baptista et al., 2004; Haddad, 2005). These differences might be due to their affinity to the H1 receptor. These atypical antipsychotics bind to the H1 receptor and express an antagonistic effect (Hirose and Kikuchi,
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a
b
Fig. 4. Histamine release in the hypothalamus after the injection of (a) risperidone (0.5 mg/kg, n ¼ 3 (Δ); 1 mg/kg, n ¼ 4 (,), i.p.) and (b) aripiprazole (1 mg/kg, n ¼ 8 (Δ); 2 mg/kg, n ¼ 6 (,), i.p.) in H1R-KO mice. The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
2005; Kroeze et al., 2003): Olanzapine and clozapine strongly bind to the H1 receptor, whereas risperidone and aripiprazole have less binding affinity (Hirose and Kikuchi, 2005; Kroeze et al., 2003). The high affinity for the H1 receptor may be a major factor underlying
a
c
atypical antipsychotic-induced obesity (Deng et al., 2010). Although risperidone and aripiprazole have H1 antagonistic effects, these drugs did not show orexigenic effects. The paradoxical finding in this study can be explained by the negligible binding affinity to the
b
d
Fig. 5. Histamine release in the hypothalamus after injection of (a) volinanserin (0.5 mg/kg, n ¼ 4 (Δ); 1 mg/kg, n ¼ 5 (,), i.p.), (b) ketanserin (5 mg/kg, n ¼ 5(Δ); 10 mg/kg, n ¼ 7 (,), i.p.), (c) SB206553 (2.5 mg/kg, n ¼ 5 (Δ); 5 mg/kg, n ¼ 5 (,), i.p.) and (d) WAY-100653 (1 mg/kg, n ¼ 6 (Δ); 2 mg/kg, n ¼ 4 (,), i.p.). The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
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H1 receptor compared to that of 5-HT receptors (Hirose and Kikuchi, 2005; Kroeze et al., 2003). In conclusion, the antagonistic effects of atypical antipsychotics on 5-HT2 receptor subtypes enhance the central histaminergic tone, resulting in excessive histamine release, which suppresses feeding behavior via the H1 receptor. References Asarian, L., Langhans, W., 2010. A new look on brain mechanisms of acute illness anorexia. Physiol. Behav. 100 (5), 464e471. Baptista, T., Zárate, J., Joober, R., Colasante, C., Beaulieu, S., Páez, X., Hernández, L., 2004. Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics. Curr. Drug Targets 5, 279e299. Deng, C., Weston-Green, K., Huang, X.F., 2010. The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1e4. Eriksson, K.S., Stevens, D.R., Haas, H.L., 2001. Serotonin excites tuberomammillary neurons by activation of Naþ/Ca2þ-exchange. Neuropharmacology 40 (3), 345e351. Eriksson, K.S., Sergeeva, O.A., Stevens, D.R., Haas, H.L., 2002. Neurotransmitterinduced activation of sodiumecalcium exchange causes neuronal excitation. Ann. N.Y. Acad. Sci. 976, 405e407. Glowinski, J., Iversen, L.L., 1966. Regional studies of catecholamines in the rat brain. I. The disposition of 3H norepinephrine, 3H dopamine and 3H dopa in various regions of the brain. J. Neurochem. 13, 655e669. Haddad, P., 2005. Weight change with atypical antipsychotics in the treatment of schizophrenia. J. Psychopharmacol. 19, 16e27. Hirose, T., Kikuchi, T., 2005. Aripiprazole, a novel antipsychotic agent: dopamine D2 receptor partial agonist. J. Med. Invest. 52 (Suppl.), 284e290. Inoue, I., Yanai, K., Kitamura, D., Taniuchi, I., Kobayashi, T., Niimura, K., Watanabe, T., Watanabe, T., 1996. Impaired locomotor activity and exploratory behavior in mice lacking histamine H1 receptors. Proc. Natl. Acad. Sci. U.S.A. 93, 13316e13320. Ishizuka, T., Hatano, K., Murotani, T., Yamatodani, A., 2008. Comparison of the effect of an H3-inverse agonist on energy intake and hypothalamic histamine release in normal mice and leptin resistant mice with high fat diet-induced obesity. Behav. Brain. Res. 188, 250e254. Ito, C., Onodera, K., Yamatodani, A., Yanai, K., Sakurai, E., Sato, M., Watanabe, T., 1997. The effect of haloperidol on the histaminergic neuron system in the rat brain. Tohoku J. Exp. Med. 183, 285e292. Itowi, N., Nagai, K., Nakagawa, H., Watanabe, T., Wada, H., 1988. Changes in the feeding behavior of rats elicited by histamine infusion. Physiol. Behav. 44, 221e226. , D., Josko, J., Drab, J., Jochem, J., Nowak, P., Szkilnik, R., Korossy-Mruk, E., Boron Kostrzewa, R.M., Brus, H., Brus, R., Sep 14 2010. Ontogenetic serotoninergic lesioning alters histaminergic activity in rats in adulthood. Neurotox. Res.. doi:10.1007/s12640-010-9217-8 URL: http://www.springerlink.com/content/c4 4209j7235rg160/. Kroeze, W.K., Hufeisen, S.J., Popadak, B.A., Renock, S.M., Steinberg, S., Ernsberger, P., Jayathilake, K., Meltzer, H.Y., Roth, B.L., 2003. H1-histamine receptor affinity
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predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519e526. Lecklin, A., Etu-Seppälä, P., Stark, H., Tuomisto, L., 1998. Effects of intracerebroventricularly infused histamine and selective H1, H2 and H3 agonists on food and water intake and urine flow in Wistar rats. Brain Res. 793, 279e288. Madhusoodanan, S., Brenner, R., Gupta, S., Reddy, H., Bogunovic, O., 2004. Clinical experience with aripiprazole treatment in ten elderly patients with schizophrenia or schizoaffective disorder: retrospective case studies. CNS Spectr. 9, 862e867. Mochizuki, T., Yamatodani, A., Okakura, K., Takemura, M., Inagaki, N., Wada, H., 1991. In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis. Naunyn. Schmiedebergs. Arch. Pharmacol. 343, 190e195. Morimoto, T., Yamamoto, Y., Mobarakeh, J.I., Yanai, K., Watanabe, T., Watanabe, T., Yamatodani, A., 1999. Involvement of the histaminergic system in leptininduced suppression of food intake. Physiol. Behav. 67, 679e683. Morimoto, T., Yamamoto, Y., Yamatodani, A., 2001. Brain histamine and feeding behavior. Behav. Brain Res. 124, 145e150. Morisset, S., Sahm, U.G., Traiffort, E., Tardivel-Lacombe, J., Arrang, J.M., Schwartz, J.C., 1999. Atypical neuroleptics enhance histamine turnover in brain via 5hydroxytryptamine2A receptor blockade. J. Pharmacol. Exp. Ther. 288, 590e596. Murotani, T., Ishizuka, T., Hattori, S., Hashimoto, R., Matsuzaki, S., Yamatodani, A., 2007. High dopamine turnover in the brains of Sandy mice. Neurosci. Lett. 421, 47e51. Oishi, R., Itoh, Y., Saeki, K., 1992. Inhibition of histamine turnover by 8-OH-DPAT, buspirone and 5-hydroxytryptophan in the mouse and rat brain. Naunyn. Schmiedebergs. Arch. Pharmacol. 345 (5), 495e499. Orthen-Gambill, N., 1988. Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats. Pharmacol. Biochem. Behav. 31, 81e86. Orthen-Gambill, N., Salomon, M., 1992. FMH-induced decrease in central histamine levels produces increased feeding and body weight in rats. Physiol. Behav. 51, 891e893. Ota, M., Mori, K., Nakashima, A., Kaneko, Y.S., Fujiwara, K., Itoh, M., Nagasaka, A., Ota, A., 2002. Peripheral injection of risperidone, an atypical antipsychotic, alters the bodyweight gain of rats. Clin. Exp. Pharmacol. Physiol. 29, 980e989. Paxinos, G., Franklin, K.B.J., 2001. The Mouse Brain in Stereotaxic Coordinates. Academic Press, San Diego. Sergeeva, O.A., Amberger, B.T., Eriksson, K.S., Scherer, A., Haas, H.L., 2003. Coordinated expression of 5-HT2C receptors with the NCX1 Naþ/Ca2þ exchanger in histaminergic neurones. Biochem. Behav. 66, 189e197. Sheiner, J.B., Morris, P., Anderson, G.H., 1985. Food intake suppression by histidine. Pharmacol. Biochem. Behav. 23, 721e726. Terao, T., 2008. Unusual weight fluctuation under corticosteroid and psychotropic treatment. Psychiatry Clin. Neurosci. 62, 617e619. Vaziri, P., Dang, K., Anderson, G.H., 1997. Evidence for histamine involvement in the effect of histidine loads on food and water intake in rats. J. Nutr. 127, 1519e1526. Wada, H., Inagaki, N., Itowi, N., Yamatodani, A., 1991. Histaminergic neuron system in the brain: distribution and possible functions. Brain Res. Bull. 27 (3e4), 367e370. Yamatodani, A., Fukuda, H., Wada, H., Iwaeda, T., Watanabe, T., 1985. High-performance liquid chromatographic determination of plasma and brain histamine without previous purification of biological samples: cation-exchange chromatography coupled with post-column derivatization fluorometry. J. Chromatogr. 344, 115e123. Yoshimatsu, H., Chiba, S., Tajima, D., Akehi, Y., Sakata, T., 2002. Histidine suppresses food intake through its conversion into neuronal histamine. Exp. Biol. Med. (Maywood) 227, 63e68.
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system Tomotaka Murotani a, *, Tomoko Ishizuka b, Yuka Isogawa a, Michitaka Karashima a, Atsushi Yamatodani a a b
Department of Medical Science and Technology, Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan Department of Pharmacology, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 February 2011 Received in revised form 1 April 2011 Accepted 7 April 2011
The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5 mg/kg, i.p.) or aripiprazole (1 mg/kg, i.p.), which have binding affinities to 5-HT1A, 2A, 2B and 2C receptors decreased food intake in C57BL/6 N mice with concomitant increase of hypothalamic histamine release. However, a selective D2-antagonist, haloperidol (0.5 mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H1 receptordeficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT2A-antagonists, volinanserin (0.5, 1 mg/kg, i.p.) and ketanserin (5, 10 mg/kg, i.p.), significantly increased histamine release and 5-HT2B/2C -antagonist, SB206553 (2.5, 5 mg/kg, i.p.), slightly increased it. On the contrary, 5-HT1A -selective antagonist, WAY100635 (1, 2 mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT2 receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT2 receptors resulting in anorexia via the H1 receptor. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Histamine H1 receptor 5-HT receptor Anorexia Schizophrenia Antischizophrenic drugs
1. Introduction The central histaminergic system has been shown to be involved in the regulation of various physiological functions including feeding behavior (Morimoto et al., 2001; Wada et al., 1991). The intracerebroventricular injection of histamine (Itowi et al., 1988; Lecklin et al., 1998) or the peripheral injection of L-histidine, the precursor of histamine (Orthen-Gambill, 1988; Sheiner et al., 1985; Vaziri et al., 1997; Yoshimatsu et al., 2002) decreased food intake, while depletion of neuronal histamine by a-fluoromethylhistidine, a specific inhibitor of histamine-forming enzyme, increased food intake (Morimoto et al., 1999; Orthen-Gambill and Salomon, 1992).
Abbreviations: 5-HT, serotonin; DOI, 2,5-dimethoxy-4-iodoamphetamine; H1RKO, H1 receptor-knock out mice; HPLC, high-performance liquid chromatography; WT, wild type; ANOVA, analysis of variance. * Corresponding author. Present address: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Kobe, Hyogo 650-0017, Japan. Tel.: þ81 78 382 6287; fax: þ81 78 382 2562. E-mail address: [email protected] (T. Murotani). 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.04.003
Furthermore, we recently reported that the peripheral injection of clobenpropit, an H3-antagonist, which increases histamine release in the brain, decreases food intake (Ishizuka et al., 2008). Lecklin et al. (1998) reported that histamine- and a selective H1-agonistinduced decrease in food intake were inhibited by an H1-antagonist but not by an H2-antagonist. These findings suggest that neuronal histamine suppresses food intake via the H1 receptor. Several studies indicate the possibility that histaminergic tone is modulated by serotonin (5-HT). For example, 5-HT excites the neurons of the tuberomammillary nucleus, which contain the origin of histaminergic neurons, by activation of the Naþ/Ca2þexchange (Eriksson et al., 2001, 2002; Sergeeva et al., 2003). The 5HT receptor agonist decreased the metabolic turnover of histamine and this effect is reversed by 5-HT antagonists (Oishi et al., 1992). Chemical lesioning of the 5-HT system in the neonatal period results in the reduction of histamine concentrations in the brains of adult rats. (Josko et al., 2010). Moreover, Morisset et al. (1999) reported that atypical antipsychotics, which antagonize some 5-HT receptor subtypes, increased histamine turnover in the brain. The effect was not
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shared by conventional antipsychotics like haloperidol which have no effect on 5-HT receptors, and was reversed by a 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). These findings imply the interaction of serotonin with the histaminergic system. Modulation of feeding behavior associated with the use of atypical antipsychotics has also been reported. Ota et al. (2002) reported that administration of a relatively high dose of risperidone (0.5 mg/kg) reduces food intake leading to weight loss in rats, while a low dose of risperidone (0.005 and 0.05 mg/kg) increases food intake and enhances weight gain. In clinical reports, aripiprazole reduced body weight in schizophrenic patients (Madhusoodanan et al., 2004) and in patients who became obese during corticosteroid treatment (Terao, 2008). In the present study, we investigated the effects of a single administration of antipsychotics on food intake and on the central histamine release in mice by in vivo microdialysis. Furthermore, to clarify which subtypes of 5-HT receptors are involved in regulating histaminergic tone following antipsychotic administration, the effect of selective 5-HT-antagonists on histamine release was examined.
Histamine contents in the brain after atypical antipsychotics injection were determined during the light phase. One hour after drug injection (risperidone: 0.5 mg/kg, i.p.; aripiprazole: 1 mg/kg, i.p.; solvent, i.p.), mice were sacrificed by decapitation and then the decapitated heads were dropped directly into ice-cold water for one second to prevent neurotransmitter decay. Brains were removed from the calvarium and placed on a chilled aluminum block. The brain was dissected into ten regions (olfactory bulb; prefrontal cortex; cortex; striatum; hippocampus; thalamus; hypothalamus; midbrain; brain-stem; cerebellum) according to the Glowinski and Iversen method (Glowinski and Iversen, 1966) with a slight modification (Murotani et al., 2007). Each section of brain tissue was put into a sampling tube and 9 volumes of 2% perchloric acid solution including 1 mM EDTA-Na2 and 1 mM Na2S2O5 was added to the tube. The tissue was then homogenized with a sonicator for 5e10 s and centrifuged (10,000 g 30 min). The concentration of histamine in the supernatant was determined using the HPLC-fluorometric method described above.
2. Materials and methods
2.5. The involvement of 5-HT receptors in histamine release
2.1. Animals
The possible involvement of the serotonergic system in the antipsychoticinduced histamine release was examined in WT mice using in vivo microdialysis after i.p. injections of the following 5-HT-receptor antagonists; WAY-100635 (a selective 5-HT1A antagonist, 1 mg/kg: n ¼ 6, 2 mg/kg: n ¼ 4, SigmaeAldrich Japan, Tokyo, Japan), volinanserin (a 5-HT2A antagonist, 0.5 mg/kg: n ¼ 4, 1 mg/kg: n ¼ 5, Toronto Research Chemicals Inc., Ontario, Canada) and ketanserin (a 5-HT2A antagonist, 5 mg/kg: n ¼ 5, 10 mg/kg: n ¼ 7, SigmaeAldrich Japan, Tokyo, Japan), and SB 206553 (a 5-HT2B,2C antagonist, 2.5 mg/kg: n ¼ 4, 5 mg/kg: n ¼ 5,Tocris Bioscience, Bristol, UK).
Eight-week-old male C57BL/6N mice (wild type: WT, Japan SLC, Shizuoka, Japan) and H1 receptor-knock out mice (H1R-KO, Inoue et al., 1996) were used. Animals were kept in cages on a 12/12 h light/dark schedule (lights on, 08:00 h to 20:00 h) and maintained at 25 1 C with 50 10% humidity. All animals had free access to standard pelleted chow (MF, Oriental Yeast, Osaka, Japan) and tap water and experiments were performed in accordance with the guidelines of the Animal Care Committee of the Graduate School for Medicine, Osaka University. Maximum effort was made to minimize the number of animals used and to limit any suffering. 2.2. Behavioral experiment The behavioral experiment was performed as described previously (Morimoto et al., 1999) with a slight modification. One week before the experiment, mice were transferred to individual glass-metabolic cages (Metabolica-MM, Sugiyama-Gen Iriki, Tokyo, Japan). During the training period, the eating time of mice was limited to 3 h after the onset of the dark phase. The amount of food intake was measured every day, and the average daily amount for 3 days before the experimental day was calculated after the daily food intake had stabilized. Following the training period, mice were intraperitoneally injected with risperidone (0.5 mg/kg, n ¼ 4), aripiprazole (1 mg/kg, n ¼ 4) and haloperidol (0.5 mg/kg, n ¼ 6) just before the onset of the dark phase. All drugs were suspended in saline containing 0.1% carboxymethyl cellulose and the same volume of solvent was injected into the control group (n ¼ 5). The ratio of food intake after drug injection to average intake was calculated. The behavioral experiment was also conducted in H1R-KO mice to examine the involvement of H1 receptor in atypical antipsychotic-induced anorexia.
was placed incorrectly were excluded from analysis. The released extracellular histamine levels in dialysate fractions were determined by high-performance liquid chromatography (HPLC) using the fluorometric method (Yamatodani et al., 1985) with slight modifications (Mochizuki et al., 1991). In each microdialysis experiment, the fractions following drug administration were expressed as a percentage of the mean of the baseline release level. 2.4. Brain histamine contents
2.6. Statistical analysis Data are presented as means and S.E.M. As for food intake and histamine contents, the significance of differences between genotypes was analyzed by oneway analysis of variance (ANOVA). When significant main effects were found, the data were further analyzed by the post-hoc least significant difference test. For the microdialysis study, significance of differences between the basal release and subsequent fractions in each group was analyzed by one-way analysis ANOVA for repeated measures. When significant main effects were found, the data were further analyzed by the post-hoc least significant difference test. A p value < 0.05 was considered significant.
2.3. In vivo microdialysis In vivo microdialysis procedures were carried out during the light phase. Overnight-fasted mice were anesthetized with urethane (1.2 g/kg, i.p.) and placed in a stereotaxic apparatus (Kopf Instrument, Tujunga, CA, USA). A microdialysis probe (MAB6; membrane length: 1 mm; ALS/Microbiotech, Stockholm, Sweden) aimed at the anterior hypothalamus was inserted using the following coordinates: AP: 0.7; LM: 0.4; DV: 5.4 mm relative to the bregma and skull surface, according to the atlas of Paxinos and Franklin (2001). The probe was perfused with artificial cerebrospinal fluid (Mochizuki et al., 1991) at a rate of 0.8 mL/min. Following 100 min perfusion to stabilize the neurotransmitter release, dialysates were collected every 25 min. After the first three baseline samples had been collected, mice received i.p. injection of the respective drugs; risperidone (0.5 mg/kg: n ¼ 6, 1 mg/kg, n ¼ 5, RisperdalÒ, Janssen Pharmaceutical, Tokyo, Japan), aripiprazole (1 mg/kg: n ¼ 7, 2 mg/kg: n ¼ 4, AbilifyÒ, Otsuka Pharmaceutical, Tokyo, Japan), haloperidol (0.5 mg/ kg: n ¼ 5, 1 mg/kg: n ¼ 7, Wako Pure Chemical, Osaka, Japan). The same volume of solvent was injected to the control group (n ¼ 5). Samples were collected for 175 min after the drug injection. After the microdialysis experiment, the probe was removed and the mice were perfused with 0.9% (wt/vol) saline through the left ventricle followed by 10% (vol/vol) formalin. The brains of the mice were examined for histological verification of the placement of the probe. Animals in which the probe
Fig. 1. Food intake after drug injection in WT mice (The ratio of food intake after drug injection to average intake). Risperidone (0.5 mg/kg, i.p., n ¼ 4) and aripiprazole (1 mg/ kg, i.p., n ¼ 4) significantly decreased food intake (risperidone: 68.7 9.5 %, aripiprazole: 72.7 6.8 %, p < 0.05) compared to that of the control group (99.7 2.4%, n ¼ 5). Haloperidol (0.5 mg/kg, i.p., n ¼ 6) did not change food intake (90.6 6.7%). Symbols used: ( ) risperidone; ( ) aripiprazole; (-) haloperidol; (,) control. *p < 0.05.
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histamine release (0.5 mg/kg, i.p., F(9,36) ¼ 0.78, p ¼ 0.63, n ¼ 5; 1 mg/kg, i.p., F(9,54) ¼ 1.26, p ¼ 0.28, n ¼ 7; Fig. 2c).
3. Results 3.1. Behavioral experiments in WT mice
3.3. Brain histamine concentrations In WT mice, risperidone (0.5 mg/kg, i.p.) significantly decreased the amount of food intake within 3 hours (68.7 9.5%, n ¼ 4, p < 0.05, Fig. 1) and aripiprazole (1 mg/kg, i.p.) also significantly decreased food intake (72.7 6.8%, n ¼ 4, p < 0.05, Fig. 1) compared to that in the control group (99.7 2.4%, n ¼ 5, Fig. 1). There was no significant change in the haloperidol (0.5 mg/kg, i.p.)-injected group (90.6 6.7%, n ¼ 6, Fig. 1). 3.2. In vivo microdialysis studies in WT mice I.p. injection of risperidone immediately increased histamine release in the anterior hypothalamus of WT mice, and high levels were maintained for about 3 h (0.5 mg/kg, i.p., F(9,45) ¼ 3.22, p < 0.01, n ¼ 6; 1 mg/kg, i.p., F(9.36) ¼ 17.3, p < 0.01, n ¼ 5; Fig. 2a). Similarly, the injection of aripiprazole significantly increased histamine release (1 mg/kg, i.p., F(9,54) ¼ 3.42, p < 0.01, n ¼ 7; 2 mg/kg, i.p., F(9,27) ¼ 6.51, p < 0.01, n ¼ 4; Fig. 2b), but the percentage of increase compared to basal release was lower than that induced by risperidone. Haloperidol had no effect on
a
Risperidone (0.5 mg/kg, i.p.) and aripiprazole (1 mg/kg, i.p.) injected at the same dose that increased histamine release on microdialysis study did not change the histamine concentration in the brain compared to that in the control (Table 1). 3.4. Behavioral experiments in H1R-KO mice In H1R-KO mice, there were no significant differences in food intake among the risperidone group (0.5 mg/kg, i.p.), aripiprazole group (1 mg/kg, i.p.) and control group (risperidone: 98.3 10.8%, n ¼ 4; aripiprazole: 96.3 10.5%, n ¼ 4, control: 108.6 12.0%, n ¼ 4, Fig. 3) (F(2,9) ¼ 1.40, p ¼ 0.30, Fig. 3). 3.5. In vivo microdialysis studies in H1R-KO mice I.p. injection of risperidone increased histamine release in the anterior hypothalamus of H1R-KO mice (0.5 mg/kg, i.p., F(9,18) ¼ 4.53, p < 0.01, n ¼ 3; 1 mg/kg, i.p., F(9,27) ¼ 7.97, p < 0.01, n ¼ 4,
b
c
Fig. 2. Histamine release in the WT mouse hypothalamus after injection of (a) risperidone (0.5 mg/kg, n ¼ 6 (Δ); 1 mg/kg, n ¼ 5 (,), i.p.), (b) aripiprazole (1 mg/kg, n ¼ 7 (Δ); 2 mg/ kg, n ¼ 4 (,), i.p.) and (c) haloperidol (0.5 mg/kg, n ¼ 5 (Δ); 1 mg/kg, n ¼ 7 (,), i.p.). The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
T. Murotani et al. / Neuropharmacology 61 (2011) 228e233 Table 1 Histamine concentrations in the brain after atypical antipsychotic injection.
Olfactory bulb Prefrontal cortex Cortex Striatum Hippocampus Thalamus Hypothalamus Midbrain Brainstem Cerebellum
Control
Risperidone (0.5 mg/kg)
Aripiprazole (1 mg/kg)
n ¼ 4w5
n ¼ 6w7
n ¼ 3w4
190.2 25.6 236.1 12.6 150.8 22.7 187.1 11.8 91.1 9.8 303.0 20.4 694.6 85.9 330.3 49.3 61.2 6.6 168.9 39.1
211.8 28.9 241.7 29.0 150.1 9.0 195.1 6.9 81.6 5.6 294.6 72.9 590.1 56.6 245.0 23.4 73.0 7.6 163.1 11.8
184.9 25.6 255.5 15.0 178.2 3.4 210.1 24.9 104.8 24.6 298.6 34.2 682.9 182.6 295.1 82.6 66.6 14.3 178.0 29.1
All data are presented as means S.E.M. (pmol/g).
Fig. 4a). The injection of aripiprazole significantly increased histamine release (1 mg/kg, i.p., F(9,63) ¼ 2.85, p < 0.01, n ¼ 8; 2 mg/kg, i.p., F(9,45) ¼ 3.69, p < 0.01, n ¼ 6, Fig. 4b) although the effect was not as remarkable as that of risperidone. 3.6. The involvement of 5-HT receptors in histamine release I.p. injection of volinanserin significantly increased histamine release in the anterior hypothalamus of WT mice (0.5 mg/kg, F(9,27) ¼ 12.2, p < 0.01, n ¼ 4; 1 mg/kg, F(9,36) ¼ 5.23, p < 0.01, n ¼ 5; Fig. 5a), and the injection of ketanserin also increased histamine release (5 mg/kg, F(9,36) ¼ 2.94, p < 0.05, n ¼ 5; 10 mg/ kg, F(9,54) ¼ 2.64, p < 0.05, n ¼ 7; Fig. 5b). SB 206553 significantly increased histamine release (2.5 mg/kg, i.p., F(9,36) ¼ 4.18, p < 0.01, n ¼ 4; 5 mg/kg, F(9,36) ¼ 3.18, p < 0.01, n ¼ 5; Fig. 5c), although the percentage of increase was small. Contrarily, i.p. injection of WAY100635 had no effect on histamine release (1 mg/kg, F(9,45) ¼ 1.15, p ¼ 0.35, n ¼ 6; 2 mg/kg, F(9,27) ¼ 0.98, p ¼ 0.48, n ¼ 4; Fig. 5d). 4. Discussion In the present study, food intake was decreased by administration of atypical antipsychotics, risperidone (0.5 mg/kg) and aripiprazole
Fig. 3. Food intake after drug injection in H1R-KO mice (The ratio of food intake after drug injection to average intake). ANOVA did not demonstrate a significant main effect of atypical antipsychotics on food intake (F(2,9) ¼ 1.40, p ¼ 0.30). Symbols used: ( ) risperidone (0.5 mg/kg, 98.3 10.8%, n ¼ 4); ( ) aripiprazole (1 mg/kg, 96.3 10.5%, n ¼ 4); (,) control (108.6 12.0%, n ¼ 4).
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(1 mg/kg) in WT mice (Fig. 1). These findings are partially consistent with the previous study that chronic administration of a relatively high dose of risperidone (0.5 mg/kg, 2weeks) gradually decreased food intake in rats but a low dose did not (0.005, 0.05 mg/kg) (Ota et al., 2002). Histamine release in the hypothalamus was significantly increased by the administration of risperidone (0.5, 1 mg/kg, Fig. 2a) and aripiprazole (1, 2 mg/kg, Fig. 2b) in WT mice. On the contrary, haloperidol (0.5, 1 mg/kg) did not modulate histamine release (Fig. 2c), which agrees with the findings of a previous report indicating that atypical antipsychotics including risperidone increased metabolic turnover of histamine in the brain (Morisset et al., 1999), and that the histaminergic tone was not changed by haloperidol even at higher doses (5, 10 mg/kg) (Ito et al., 1997). The present findings demonstrate that risperidone and aripiprazole at the dose used increased hypothalamic histaminergic activity without modulating the histamine concentration (Table 1), which reflects histamine synthesis or metabolism in the brain. In contrast to the findings in WT mice, the same dose of risperidone and aripiprazole did not induce anorexia in H1R-KO mice (Fig. 3) although increased histamine release induced by these antipsychotics was observed (Fig. 4a and b). Central histamine suppresses feeding behavior via the H1 receptor (Morimoto et al., 2001) and H1RKO mice showed a normal increase in histamine release after risperidone and aripiprazole injection in the present study. Thus, hypothalamic histamine release responds to atypical antipsychotics in H1R-KO mice; however, these animals do not develop drug-related anorexia because they are devoid of H1 receptors. Selective 5-HT2A antagonists, volinanserin (0.5, 1 mg/kg, Fig. 5a) and ketanserin (5, 10 mg/kg, Fig. 5b), and the 5-HT2B, 2C antagonist, SB206553 (2.5, 5 mg/kg, Fig. 5c) significantly increased the histamine release. However, the selective 5-HT1A antagonist, WAY-100635 (1, 2 mg/kg, Fig. 5d), did not have any effects on histamine release. These findings indicate that the release of central histamine was modulated by 5-HTergic transmission via 5-HT2A and 5-HT2B, 2C receptors but not via 5-HT1A receptor. Between these three receptors, the 5-HT2A receptor may be the more likely candidate to regulate histamine release based on a comparison of the efficacy of antagonists (Fig. 5a and b vs. Fig. 5c). Previous reports demonstrated that risperidone has a higher affinity to 5-HT2 receptor subtypes than to 5-HT1A receptor in contrast to aripiprazole, which has a higher affinity to the 5-HT1A receptor (Kroeze et al., 2003; Hirose and Kikuchi, 2005). These differences in binding affinity to 5-HT receptor subtypes between risperidone and aripiprazole might have contributed to differences in the efficacy in releasing histamine in the present study. Morisset et al. (1999) reported that atypical antipsychotics including clozapine, olanzapine, risperidone, thioridazine, seroquel and iloperiodone increased metabolic turnover of histamine in the brain. The effect was not shared by haloperidol, sulpiride, raclopride and remoxipride, and was reversed by a 5-HT2A receptor agonist, DOI. Based on these findings, they concluded that atypical antipsychotics stimulate histamine neuronal activity via blockade of the 5-HT2A receptor, which is consistent with the present findings. 5-HT have direct or indirect influence on feeding behavior. The fact that patient with anorexia nervosa have abnormality in their expression of 5-HT receptor (Asarian and Langhans, 2010) is good example which suggests a certain connection between 5-HT and appetite. Thus, further study to clarify the effects of 5-HT2 antagonists themselves on food intake is needed. Risperidone and aripiprazole have less potential to cause druginduced weight gain than olanzapine and clozapine (Baptista et al., 2004; Haddad, 2005). These differences might be due to their affinity to the H1 receptor. These atypical antipsychotics bind to the H1 receptor and express an antagonistic effect (Hirose and Kikuchi,
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a
b
Fig. 4. Histamine release in the hypothalamus after the injection of (a) risperidone (0.5 mg/kg, n ¼ 3 (Δ); 1 mg/kg, n ¼ 4 (,), i.p.) and (b) aripiprazole (1 mg/kg, n ¼ 8 (Δ); 2 mg/kg, n ¼ 6 (,), i.p.) in H1R-KO mice. The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
2005; Kroeze et al., 2003): Olanzapine and clozapine strongly bind to the H1 receptor, whereas risperidone and aripiprazole have less binding affinity (Hirose and Kikuchi, 2005; Kroeze et al., 2003). The high affinity for the H1 receptor may be a major factor underlying
a
c
atypical antipsychotic-induced obesity (Deng et al., 2010). Although risperidone and aripiprazole have H1 antagonistic effects, these drugs did not show orexigenic effects. The paradoxical finding in this study can be explained by the negligible binding affinity to the
b
d
Fig. 5. Histamine release in the hypothalamus after injection of (a) volinanserin (0.5 mg/kg, n ¼ 4 (Δ); 1 mg/kg, n ¼ 5 (,), i.p.), (b) ketanserin (5 mg/kg, n ¼ 5(Δ); 10 mg/kg, n ¼ 7 (,), i.p.), (c) SB206553 (2.5 mg/kg, n ¼ 5 (Δ); 5 mg/kg, n ¼ 5 (,), i.p.) and (d) WAY-100653 (1 mg/kg, n ¼ 6 (Δ); 2 mg/kg, n ¼ 4 (,), i.p.). The mean values are presented as percentages of the mean basal release and S.E.M. **p < 0.05, *p < 0.01 compared with the basal release in each group. (C): control.
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