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Home , Dopamine agonist, Ocaperidone, Ritanserin

Effects of on -Induced Behaviors: Comparison with and

Kiyoyuki Kitaichi', Kiyofumi Yamada', Takaaki Hasegawa', Hiroshi Furukawa2 and Toshitaka Nabeshima',* 'Department of Neuropsychopharmacology and Hospital Pharmacy , Nagoya University School of Medicine, Nagoya 466, Japan 2Department of Medicinal Chemistry , Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan

Received April 25, 1994 Accepted June 24, 1994

ABSTRACT-In this study, we investigated whether risperidone, a -S2A (5-HT21)/-D2 (D2)- antagonist, inhibits phencyclidine (PCP)-induced stereotyped behaviors in comparison with haloperidol and ritanserin. Moreover, we also attempted to investigate the effects of these on the contents of dopamine, serotonin (5-HT) and their metabolites in rat striatum and frontal cortex. In rats, PCP (5 mg/kg, i.p.) caused hyperlocomotion and stereotyped behaviors, including sniffing, head-weaving, backpedalling and turning. Both risperidone (0.8-2.4 mg/kg, p.o.) and haloperidol (0.3-1.0 mg/kg, p.o.) inhibited these behaviors, except for backpedalling, in a dose-dependent manner. PCP (10 mg/kg, i.p.) pro duced hyperlocomotion and stereotyped behaviors, including rearing, sniffing head-twitch, backpedalling and turning. Risperidone (0.8-2.4 mg/kg, p.o.) inhibited both hyperlocomotion and PCP-induced behaviors, except for backpedalling, while ritanserin (3 -10 mg/kg, p.o.) inhibited only the head-twitch. These results suggest that risperidone may have an effect on as well as PCP in humans by exerting a mixed 5-HT2A/D2 antagonism. Neurochemically, the increasing effects of risperidone on the content of DOPAC and the ratio of DOPAC to dopamine in the striatum were lower than those of haloperidol. These findings may support the view that the extrapyramidal side effects of risperidone are lower than those of haloperidol in clinical situations.

Keywords: Risperidone, Mixed 5-HT2A/D2 antagonist, Phencyclidine, Stereotyped behavior

It is well known that typical antipsychotics have benefi vide a good animal model of schizophrenia that includes cial effects on the positive symptoms of schizophrenia, the negative symptoms (7-9). but not on the negative symptoms (1). Many investigators In animals, PCP causes stereotyped behaviors (10 12) have already reported that the blockade of both dopa as other psychostimulants do. In previous experiments, minergic and neuronal systems may be im we reported that the hyperlocomotion and some of stereo portant for the treatment of both positive and negative typed behaviors induced by PCP were mediated by dopa symptoms of schizophrenia: clinically, 1) and minergic and serotonergic neuronal systems and that , both which are potent serotonin-S2A (5-HT2A) PCP-induced head-twitch via 5-HT2A receptors in rats receptor antagonists with a relatively lower dopamine (13-16). Therefore, several investigators including us D2 (D2)-receptor antagonistic property, are effective in hypothesized that the that block both PCP-induced both the positive and negative symptoms of schizophrenia dopamine and 5-HT-mediated stereotyped behaviors (2-4), and 2) ritanserin, a 5-HT2A-, may possibly prevent both the positive and negative symp reinforces the antipsychotic effects of haloperidol, particu toms of schizophrenia (7 9). larly on the negative symptoms (5). Risperidone is a potent D2-receptor antagonist with a In normal individuals, phencyclidine (1-(1-phenylcyclo predominant, concomitant 5-HT2A antagonistic activity hexyl)piperidine hydrochloride, angel dust, PCP) induces (17, 18). In clinical use, it has been reported that risperi a schizophrenia-like syndrome including both positive done improves both the negative and positive symptoms and negative symptoms (6, 7). Therefore, PCP may pro of schizophrenia with the relative absence of extrapyrami dal side effects (19). In this study, we investigated whether the concomitant blockade of D2-receptors and 5-HT2A-receptors by risperi haloperidol on the head-weaving, and PCP at 10 mg/kg, done inhibits PCP-induced stereotyped behavior in rats i.p. was used to evaluate the blocking effects of risperi in comparison with the D2-receptor antagonist halo done and ritanserin on head-twitch. Other behaviors peridol and the 5-HT2A-receptor antagonist ritanserin. (hyperlocomotion, rearing, sniffing, backpedalling and Moreover, we attempted to investigate the effects of these turning) were measured in rats treated with both doses of antipsychotics on the contents of monoamines and their PCP, because the effects of risperidone on them were com metabolites in the rat striatum and frontal cortex. pared to those of haloperidol and ritanserin. Rats were challenged with PCP (5 or 10 mg/kg, i.p.) 1 MATERIALS AND METHODS hr after pretreatment with vehicle or drugs; and then the hyperlocomotion and stereotyped behaviors, i.e., rearing, Animals sniffing, head-weaving, head-twitch, backpedalling and Male Kbl Wistar rats (Oriental Bio Service Co., Ltd., turning were measured for 90 min as described by Kyoto), weighing 200 to 300 g, were used. The animals Nabeshima et al. (8, 15). Briefly, hyperlocomotion was were maintained in a temperature and humidity-regulat measured automatically over a 90-min period by using ed room (22-241C, 55-L5016) with controlled lighting electric digital counters with infrared cell sensors placed (light on 9:00 to 21:00) for at least 3 days before the ex on the walls (SCANET SV-10; Toyo Sangyou, Toyama). periment. The stereotyped behaviors were rated as follows: rearing (number of times the animal stood on its hind legs), Drugs sniffing (0, absent; 1, occasional; 2, frequent; 3, con The following drugs were used: phencyclidine stant), head-weaving (number of times the animal made hydrochloride (PCP, synthesized by us) was dissolved in slow, side-to-side head movements), head-twitch (number 0.9010 saline. Risperidone (Janssen Kyowa, Tokyo) and of times the animal exhibited rapid lateral twitching of ritanserin (Janssen Kyowa) were dissolved in distilled the head similar to the pinna reflex), backpedalling (num water containing 2 equivalents of tartaric acid. Haloper ber of times the animal made backward locomotion), and idol (Sigma, St. Louis, MO, USA) was dissolved in dis turning (the number of times the animal circled laterally tilled water containing an equivalent of tartaric acid. In to the left or right over 360° within a relatively small the behavioral study, PCP was injected i.p. (0.2 ml/100 g area). Rating for rearing, backpedalling and turning was body weight) and the other drugs and vehicle were given made over a 90-min observation period. Rating for head p.o. (0.2 ml/100 g body weight) 1 hr before the injection weaving and head-twitch was made over a 3-min obser of PCP. vation period every 15 min for 78 min postinjection. Sniffing was scored over a 1-min observation period every Behavioral studies 15 min for 76 min postinjection. The doses of oral ad All behavioral experiments were conducted between ministration for haloperidol and ritanserin were approxi 11:00 and 19:00; the room temperature was 22-241C. mately fixed at the doses that inhibited methampheta Animals were observed while they were in individual plas mine-induced hyperactivity (20) and (± )DOI ((±)-1 tic cages (30 x 35 x 17 cm). Over 2 hr after the habituation (2,5-dimethoxy-4-iodophenyl)-2-aminopropane)-induced to the test room and food-deprivation, they were habituat head-twitch (21), respectively. In preliminary experiments, ed to the cages by placing them individually for 30 min be we investigated the effects of several doses of three fore the experiments. The animals were assigned random antipsychotics, and then selected slightly and markedly ly to the different treatment groups. inhibitory doses of haloperidol and ritanserin on PCP (5 mg/kg, i.p.)-induced hyperlocomotion and PCP (10 Measurement of PCP-induced hyperlocomotion and mg/kg, i.p.)-induced head-twitch, respectively. The doses stereotyped behaviors of risperidone were selected in the same way. Nabeshima et al. (8) reported that head-weaving, which was partly mediated by both and serotoner Determination of dopamine and 5-HT and their metabo gic neuronal systems, was observed in rats treated with lites in rat brain PCP at 5 mg/kg, i.p., but scarcely seen in those treated The doses of antipsychotics were fixed as follows: 2.4 with PCP at 10 mg/kg, i.p. In contrast, they found that mg/kg for risperidone, 1.0 mg/kg for haloperidol and 10 head-twitch, which was mediated by 5-HT2A-receptors, mg/kg for ritanserin, because these doses had similar occurred in rats treated with PCP at 10 mg/kg, i.p., effects on the PCP-induced behaviors; the effects of not with PCP at 5 mg/kg, i.p. Therefore, we selected 2 risperidone (2.4 mg/kg) on some PCP-induced behaviors different doses of PCP: PCP at 5 mg/kg, i.p. was used and head-twitch were almost equal to those of to evaluate the blocking effects of risperidone and haloperidol (1.0 mg/kg) and ritanserin (10 mg/kg), respectively. Rats were injected i.p. with PCP (10 mg/kg) Statistical analyses or the vehicle 1 hr after the p.o. treatment with antipsy For the data of hyperlocomotion, rearing, head-weav chotics and decapitated 1 hr after the injection of PCP. ing, head-twitch, turning and biochemical data, overall The striatum and frontal cortex were dissected out. The group differences between the control and drug-treated samples were rapidly frozen and stored in a deep-freezer groups were determined by one-way analysis variance of at 80'C until the measurement of the monoamines and ranks (ANOVAs) and the parametric Tukey test. For the their metabolites. The content of dopamine, 3,4-dihy data of sniffing, overall group differences between the con droxyphenylacetic acid (DOPAC), homovanillic acid trol and drug-treated groups were determined by the (HVA), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) Kruskal-Wallis analysis of variance of ranks. Statistical in the striatum and frontal cortex was determined by high analysis was then carried out by the non-parametric performance liquid chromatography (HPLC) with electro Tukey test for data in which the Kruskal-Wallis H scores chemical detection according to the method of Nitta et al. were associated with a probability of less than 507o. (22).

Fig. 1. Effects of risperidone and haloperidol on PCP (5 mg/kg, Fig. 2. Effects of risperidone and haloperidol on PCP (5 mg/kg, i.p.)-induced hyperlocomotion (A) and turning (B) in rats. Rats were i.p.)-induced sniffing (A) and head-weaving (B) in rats. Rats were challenged with PCP 60 min after the p.o. treatment with vehicle, challenged with PCP 60 min after the p.o. treatment with vehicle, risperidone or haloperidol, and then hyperlocomotion and turning risperidone or haloperidol, and then sniffing and head-weaving were were measured for 90 min. Each column represents the mean -h S. E. measured for 90 min. Each point represents the mean from 8 rats. from 9 to 15 rats. Motility counts of the vehicle+saline-treated 0: vehicle; EI: risperidone, 0.8 mg/kg; •: risperidone, 2.4 mg/kg; group were 1324±350. *P<0.05, **P<0.01 vs. vehicle-treated A: haloperidol, 0.3 mg/kg; A: haloperidol, 1.0 mg/kg. *P<0.05, group (Tukey test). **P<0 .01 vs. vehicle-treated group (Tukey test). RESULTS

Effects of risperidone and haloperidol on PCP (5 mg/kg, i.p.)-induced hyperlocomotion and stereotyped behaviors in rats PCP (5 mg/kg) produced locomotor stimulation (hyperlocomotion), but not rearing. PCP (5 mg/kg)-in duced hyperlocomotion was inhibited by risperidone (0.8 and 2.4 mg/kg) and haloperidol (0.3 and 1.0 mg/kg) in a dose-dependent manner (Fig. IA) without affecting PCP-induced ataxia (data not shown). Risperidone (2.4 mg/kg) and haloperidol (1.0 mg/kg) produced significant

Fig. 3. Effects of risperidone and ritanserin on PCP (10 mg/kg, i.p.)-induced hyperlocomotion (A), rearing (B) and turning (c) in Fig. 4. Effects of risperidone and ritanserin on PCP (10 mg/kg, rats. Rats were challenged with PCP 60 min after the p.o. treatment i.p.)-induced sniffing (A) and head-twitch (B) in rats. Rats were with vehicle, risperidone or ritanserin, and then hyperlocomotion, challenged with PCP 60 min after the p.o. treatment with vehicle, rearing and turning were measured for 90 min. Each column risperidone or ritanserin, and then sniffing and head-twitch were represents the mean±S.E. from 8 to 12 rats. Motility counts and measured for 90 min. Each point represents the mean from 6 rats. number of rearings of the vehicle + saline-treated group were 0: vehicle; EI: risperidone, 0.8 mg/kg; N: risperidone, 2.4 mg/kg; 1128±426 and 7.6±3.6, respectively. *P<0.05, **P<0.01 vs. vehi A: ritanserin, 3mg/kg; A: ritanserin, 10mg/kg. *P<0.05, cle-treated group (Tukey test). **P < 0.01 vs. vehicle-treated group (Tukey test). effects. Moreover, risperidone (0.8 and 2.4 mg/kg) and Effects of risperidone and ritanserin on PCP (10 mg/kg, haloperidol (1.0 mg/kg) reduced the score for PCP-in i.p.)-induced hyperlocomotion and stereotyped behaviors duced turning (Fig. 1B). However, these drugs failed to in rats inhibit the backpedalling induced by PCP (data not As shown in Fig. 3A, the hyperlocomotion induced by shown). In addition, PCP (5 mg/kg)-induced sniffing and PCP (10 mg/kg) was inhibited by risperidone (0.8 and head-weaving were also inhibited by risperidone and 2.4 mg/kg) in a dose-dependent manner, but not ritanse haloperidol (Fig. 2, A and B). The treatment of these anti rin (3 and 10 mg/kg) and both antipsychotics failed to psychotics failed to affect the locomotion and the score of affect PCP-induced ataxia (data not shown). Risperidone rearing and sniffing of naive rats (data not shown). (0.8 and 2.4 mg/kg) reduced the score for PCP (10 mg/kg)-induced rearing (Fig. 3B), turning (Fig. 3C) and sniffing (Fig. 4A). In contrast, the score for PCP-induced

Table 1. Effects of risperidone, haloperidol and ritanserin in combination with saline or PCP (10 mg/kg, i.p.) on the contents of monoamines and their metabolites and monoamine turnover in the striatum

Table 2. Effects of risperidone, haloperidol and ritanserin in combination with saline or PCP (10 mg/kg, i.p.) on the contents of monoamines and their metabolites and monoamine turnover in the frontal cortex rearing, sniffing or turning was not altered by ritanserin while serotonergic neuronal systems also play an im (3 and 10 mg/kg). Both risperidone and ritanserin failed portant role in PCP-induced head-weaving (8). to alter the score for PCP-induced backpedalling (data Our present results showed that risperidone, like not shown). As shown in Fig. 4B, the score for the PCP haloperidol, inhibited PCP-induced hyperlocomotion induced head-twitch was significantly inhibited by both and stereotyped behaviors such as rearing, sniffing, head risperidone and ritanserin in a dose-dependent manner. weaving and turning. Moreover, the oral dose levels of The score of the head-weaving induced by PCP was so risperidone and haloperidol used in this study approxi low that the effect of risperidone and ritanserin could not mately equaled the 50% inhibitory doses for apomor be determined (data not shown). phine-induced agitation of risperidone (approximately 1.8 mg/kg) and haloperidol (approximately 0.7 mg/kg) Effects of risperidone, haloperidol and ritanserin on dopa (31). Therefore, it is suggested that risperidone have mine turnover and contents of 5-HT and 5-HIAA in rat inhibitory effects on such PCP-induced behaviors by brain blocking D2-receptors. These results are consistent with As shown in Table 1, risperidone (2.4 mg/kg) and the following reports that risperidone inhibits both the haloperidol (1.0 mg/kg), when they were administered stereotyped behavior and hyperactivity induced by the alone or in combination with PCP (10 mg/kg), increased dopamine releaser (32) and the agitation both the contents of DOPAC and HVA and the ratio of induced by the dopamine (31). DOPAC to dopamine and HVA to dopamine in the stria In vitro, PCP was found to inhibit the specific binding tum. The increasing effect of risperidone (2.4 mg/kg) on of [3H]- to 5-HT2A-receptors in a study using rat the contents of DOPAC (P<0.01) and the ratio of synaptic membrane (33, 34). Behaviorally, both PCP at a DOPAC to dopamine (P<0.01) in the striatum of PCP high dose (10 mg/kg, i.p.) and the 5-HT releaser p-chlo treated rats was significantly lower than that of roamphetamine induce head-twitch (Fig. 4, ref. 8). This haloperidol (1.0 mg/kg). In contrast, risperidone (2.4 head-twitch is enhanced 2 weeks after the injection of the mg/kg) in combination with PCP increased both the con 5-HT-neurotoxin, 5,7-dihydroxytryptamine with the in tents of DOPAC and HVA and the ratio of DOPAC to do crement of 5-HT2A-receptors (8). Furthermore, in rats pamine and HVA to dopamine in the frontal cortex, but that have received repeated administrations of PCP, toler the combination with haloperidol (1.0 mg/kg) did not ance is developed in the serotonergic neuronal system: the (Table 2). Ritanserin (10 mg/kg) with or without PCP did [3H]-spiperone binding capacity is reduced (34), and the not modify the contents of dopamine and their metabo frequency of PCP-induced head-twitch is decreased (15). lites and dopamine turnover in either the striatum or fron These results suggest that PCP induces head-twitch via tal cortex (Tables 1 and 2). Moreover, both the contents postsynaptic 5-HT2A-receptors. In the present experi of 5-HT and their metabolites and serotonin turnover in ments, the head-twitch induced by PCP (10 mg/kg) was the striatum and frontal cortex were not modified by these blocked by the oral administration of risperidone (0.8 antipsychotics, with the exception of haloperidol (1.0 and 2.4 mg/kg) and ritanserin (10 mg/kg). The oral doses mg/kg) in combination with PCP. of risperidone and ritanserin used in this study seem to be high, because Janssen et al. (18) have reported that the DISCUSSION 50% inhibitory s.c. doses of risperidone and ritanserin on 5-hydroxytryptophan-induced head-twitch was 0.016 and Many studies including our recent one suggested that 0.074 mg/kg, respectively. These discrepancies resulted dopaminergic neuronal systems play a very important from the differences of the drug and observational time; role in the hyperlocomotion, rearing, sniffing, head-weav that is, they only observed the effects over a 20-min ing and turning induced by PCP: 1) PCP-induced stereo period, starting from 70 min after the 5-hydroxytrypto typed behaviors are enhanced by amphetamine (23, 24), phan injection, but we observed the head-twitch over a but attenuated by the dopamine-receptor antagonists 90-min period, starting from immediately after the PCP haloperidol and (25, 26); 2) PCP produces sig injection. Rinaldi-Carmona et al. (21) have shown that nificant locomotor stimulation and rearing when injected ritanserin (10 mg/kg, p.o.) inhibits the head-twich in into the nucleus accumbens (27, 28), and this effect of duced by the 5-HT2A-agonist (±)DOI, supporting that PCP is inhibited by the systemic administration of our oral dose levels of ritanserin is appropriate for the haloperidol (27, 28); and 3) bilateral lesions of the stria determination of its inhibitory effects on PCP-induced tum, made both electrically and by the dopaminergic head-twitch. Thus, our present results suggest that risperi neurotoxin 6-hydroxydopamine, reduce PCP-induced done may inhibit the PCP-induced head-twitch by block sniffing, head-weaving and turning, with the marked ing 5-HT2A-receptors. reduction of dopamine contents in the striatum (29, 30), PCP-induced backpedalling is diminished by lesions of the striatum with 5,6-dihydroxytryptamine, as well as by that sigma-receptors may play an important role in electrolytic lesion of the raphe nucleus, a region that con schizophrenia (37, 39) and that some of the sigma-recep tains 5-HT cell bodies (29, 30). Therefore, it has been sug tor ligands have the ability to change dopamine turnover gested that serotonergic neuronal systems may play an im (40, 41). Moreover, phencyclidine-induced head-weaving, portant role in PCP-induced backpedalling. However, which is partly mediated by nigrostriatal dopaminergic the backpedalling induced by PCP was not affected by neuronal systems (29, 30), was blocked by the sigma either risperidone or ritanserin. These results suggest that receptor antagonists NE-100 and BMY-14802 (42, 43) 5-HT-receptor subtypes other than 5-HT2A-receptors may Therefore, it is possible that our present results may result be more important in inducing the backpedalling. from the differences in the binding affinity for sigma In the neurochemical study, risperidone increased the receptors between risperidone and haloperidol, although degree of dopamine turnover, similarly to haloperidol, in the roles of sigma-receptors on dopamine turnover both the striatum and frontal cortex, while the effects of remain to be further elucidated. risperidone in combination with PCP on the contents of Thus, these neurochemical results taken together with DOPAC and the ratio of DOPAC to dopamine in the stria our present behavioral results suggest that risperidone has tum were significantly lower than that of haloperidol in the same inhibitory effects on PCP-induced behaviors as combination with PCP. Since Leysen et al. (35) have haloperidol with lower increasing effects on dopamine turn reported that the in vitro binding affinity of risperidone over in the striatum than haloperidol. The nigrostriatal and haloperidol for D2-receptors was exactly the same in dopaminergic neurons and mesolimbic dopaminergic neu prepared membranes from rat striatum and frontal cor rons are thought to be involved in the expression of the ex tex, it is possible that the binding capacity of risperidone trapyramidal side effects and therapeutic effects of anti and haloperidol to other kinds of receptors may be psychotics, respectively (9, 44). Risperidone is useful for responsible for the differences of dopamine turnover in the treatment of schizophrenia because it has lower ex the striatum. trapyramidal side effects than other antipsychotics in hu Two possibilities may underlie these differences be mans (19) Therefore, it is possible that the differences of tween risperidone and haloperidol. First, since risperi the present biochemical findings between risperidone and done binds to 5-HT2A-receptors more preferentially than haloperidol may indicate that risperidone has clinical D2-receptors (17), it is possible that 5-HT2A-receptors may advantages over haloperidol because it has less extra play an important role in dopamine turnover. However, pyramidal side effects. Because it has been reported that there are few reports about the interaction between D2 other neuronal systems, including ones, may receptors and 5-HT2A-receptors in dopamine turnover be involved in the extrapyramidal side effects (45-47), (35, 36), and it is difficult to compare our present results the effects of these drugs on the other neuronal systems to previous ones. For example, Leysen et al. (35) have should be further investigated. reported that there are some differences of the effects on In conclusion, it is clear that risperidone can inhibit dopamine and their metabolites in rat brain between PCP-induced stereotyped behaviors in rats, and this effect risperidone and haloperidol, although the doses of these is mediated by the blockade of both D2-receptors and 5 antipsychotics used in their study were higher than the HT2A-receptors. Therefore, these results suggest that doses that have an inhibitory effect on both dopamine risperidone may have potent antipsychotic effects on and serotonin-mediated behaviors (18, 31, 32); that is, the schizophrenia as well as PCP psychosis in humans. dose of haloperidol leading to maximal HVA levels in the striatum is almost equal to the dose producing 50% occu Acknowledgments This work was supported, in part, by Grants-in-Aid (No. pation of D2-receptors, whereas the dose of risperidone is 03304036 and No. 00092093) for Science Research from The Minis about 2 times higher than the 50% occupation dose. try of Education, Science and Culture of Japan; a Grant for Drug Saller et al. (36) have reported that the 5-HT2A-receptor Abuse Research (92-268) from The Ministry of Health and Welfare antagonist ICI 169,369 enhanced the increase of dopa of Japan; and a Grant from the Suzuken Memorial Foundation. mine metabolite levels induced by haloperidol in the stria tum, although these results are inconsistent with our REFERENCES present results. Therefore, with regards to the roles of 5 HT2A-receptors on dopamine turnover, further investiga 1 Bleich A, Brown SL, Kahn R and Van Praag HM: The role of serotonin in schizophrenia. Schizophrenia Bull 14, 297-315 tions should be carried out. Secondly, because (1988) haloperidol and phencyclidine can bind to sigma-recep 2 Ceulemans DL, Gelders YG, Hoppenbrouwers ML, Reyntjens tors (37, 38), but risperidone can not (35), it is possible AJ and Janssen PA: Effect of serotonin antagonism in that sigma-receptors may be involved in dopamine turn schizophrenia. Psychopharmacology (Berlin) 85, 329-332 over. 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