Anandamide attenuates haloperidol-induced vacuous chewing movements in rats

PNP-08592; No of Pages 5 Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2014) xxx–xxx

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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp

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Jivago Röpke a, Alcindo Busanello a, Caroline Queiroz Leal c, Elizete de Moraes Reis a, Catiuscia Molz de Freitas c, Jardel Gomes Villarinho a, Fernanda Hernandes Figueira b, Carlos Fernando Mello a, Juliano Ferreira a,b, Roselei Fachinetto a,b,⁎

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Article history: Received 9 October 2013 Received in revised form 26 March 2014 Accepted 9 April 2014 Available online xxxx

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Keywords: Anandamide Dopaminergic system Endocannabinoids Open field

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Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidolinduced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38 mg/kg, intramuscularly — i.m.). The effect of anandamide (6 nmol, intracerebroventricularly — i.c.v.) and/or the CB1 receptor antagonist SR141716A (30 μg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28 days after the start of the haloperidol treatment. Anandamide reversed haloperidolinduced VCMs; SR141716A (30 μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia. © 2014 Published by Elsevier Inc.

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Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria, RS, Brazil Curso de Farmácia, Universidade Federal de Santa Maria, RS, Brazil

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1. Introduction

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Antipsychotics are a class of drugs used for the treatment of psychiatric disorders. Current pharmacological evidence suggests that dopamine D2 receptor antagonism on the mesolimbic pathway is a major determinant of antipsychotic action (Seeman, 1987). However, antipsychotics also antagonize striatal dopamine D2 receptors in the nigrostriatal dopaminergic pathway, which have been implicated in the development of acute and chronic involuntary motor effects, of which tardive dyskinesia (TD) is the most severe (Crane, 1968; Creese et al., 1976; Kane, 1995; Tarsy and Baldessarini, 1977). TD is a syndrome characterized by involuntary orofacial movements, which can also affect the musculature of the trunk and upper and lower limbs (Egan et al., 1996). This syndrome has clinical relevance due to its high prevalence

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Anandamide attenuates haloperidol-induced vacuous chewing movements in rats

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Abbreviations: ANOVA, analysis of variance; CB1, cannabinoid receptor 1; D2, dopamine receptor 2; L-DOPA, L-3,4-dihydroxyphenylalanine; OD, orofacial dyskinesia; MAO, monoaminoxidase; PBS, phosphate buffered saline; SR141716A, 5-(4-chlorophenyl)-1(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; TD, tardive dyskinesia; VCM, vacuous chewing movements. ⁎ Corresponding author at: Centro de Ciências da Saúde, Departamento de Fisiologia e Farmacologia, 97105-900 Santa Maria, RS, Brazil. Tel.: + 55 3220 8096x21; fax: + 55 3220 8241x21. E-mail address: [email protected] (R. Fachinetto).

in humans treated with antipsychotic medications, as well as its persistence and irreversibility, even after treatment withdrawal (Casey, 1985; Crane, 1973; Jeste et al., 1979). Despite the large number of studies, the pathophysiological mechanisms of TD remain unclear, which hinders the discovery of an effective treatment. Several hypotheses have been proposed to explain the development of TD (Andreassen and Jørgensen, 2000). The classical hypothesis to explain TD is the development of dopaminergic supersensitivity, which can result from the chronic use of antipsychotics (Burt et al., 1977; Klawans and Rubovits, 1972; Rubinstein et al., 1990). Accordingly, the chronic blockage of dopamine receptors by D2 antagonists increases the number of receptors and the sensitivity of the dopaminergic receptors, culminating in a hyperdopaminergic state, which could be responsible for TD (Cavallaro and Smeraldi, 1995; Kane, 1995). However, there are inconsistencies in this hypothesis, and other alterations in the dopaminergic system have been reported. It was previously demonstrated that orofacial dyskinesia (OD), a syndrome caused by antipsychotics in rodents with similar characteristics to TD in humans, is related to a decrease in dopamine uptake in the striatum of rats treated with antipsychotics, either haloperidol or fluphenazine (Fachinetto et al., 2007a, 2007b). Accordingly, a decreased density of dopamine transporters in patients with TD has recently been reported (Rizos et al., 2010). Therefore, the elucidation of the regulatory mechanisms of striatal dopaminergic activity

http://dx.doi.org/10.1016/j.pnpbp.2014.04.006 0278-5846/© 2014 Published by Elsevier Inc.

Please cite this article as: Röpke J, et al, Anandamide attenuates haloperidol-induced vacuous chewing movements in rats, Prog NeuroPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2014.04.006

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Seventy adult male Wistar rats weighing 220 to 270 g from our own breeding colony were kept in cages with four or five animals each with continuous access to food and water. The room housing the cages was temperature-controlled (22 ± 2 °C) and on a 12-h light/dark cycle with the lights going on at 7:00 am. Each cage of animals treated with haloperidol or vehicle contributed with no more than one animal for each group injected with SR141617A or anandamide. The experimental procedure was previously approved by the Ethical Commission of Animal Use from Federal University of Santa Maria under number 050/2011.

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2.2. Drugs

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Haloperidol decanoate (Haldol®, Janssen Pharmaceutica, Turnhoutseweg, Beerse, Bélgica) was commercially acquired.

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2.3.1. Surgery Rats were anesthetized with a combination of ketamine (80 mg/kg) and xylazine (13 mg/kg) intraperitoneal (i.p.) and placed in a stereotaxic apparatus. Under stereotaxic guidance, a cannula was inserted into the right lateral ventricle (coordinates relative to bregma: AP 0 mm, ML 1.5 mm, V 2.5 mm) (Paxinos and Watson, 1986). Ceftriaxone (500 mg/kg, i.p.) was administered immediately after the surgical procedure.

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2.3.2. Effect of anandamide on spontaneous locomotion A dose–response curve for the effect of anandamide on the spontaneous locomotion of rats in an open field was performed. The animals were subjected to stereotaxic surgery to insert a cannula into the lateral ventricle, as described below. Three days after surgery, the rats were i.c.v. injected with vehicle (2% ethanol dissolved in 100 mM PBS buffer, pH = 7.4, 2.5 μL/site) or anandamide (1, 3, 6, 9 or 27 nmol/2.5 μL). Thirty seconds after the injection, the animals were placed in an open field, and the number of crossings was evaluated in a period of five minutes, as previously described by Broadhurst (1960). The maximal dose that did not cause any significant effect on spontaneous locomotor activity was selected for the subsequent experiments. We used the i.c.v. administration to guarantee more precise control of the amount of drug delivered to the central nervous system and also avoid the peripheral effects of anandamide.

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Anandamide (N-arachidonoylethanolamine), SR141617A and all other 134 drugs were purchased from Sigma (St. Louis, MO). 135

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2.3.3. Haloperidol-induced vacuous chewing movements The animals received a single intramuscular (i.m.) administration of vehicle (soy oil, 1 mL/kg) or haloperidol decanoate (Haldol®), a slowreleasing preparation of haloperidol at a dose of 38 mg/kg, which is equivalent to 1 mg/kg/day of unconjugated haloperidol (Fachinetto et al., 2007a). Twenty-four days later, the animals were subjected to stereotaxic surgery to insert a cannula into the lateral ventricle as described below. Three days after surgery, the animals were individually placed in cages (20 × 20 × 19 cm). After a 6-min habituation period, the number of VCMs was counted for an additional 6 min (Fig. 1), as previously described (Busanello et al., 2012; Fachinetto et al., 2005, 2007a). VCMs were defined as single mouth openings in the vertical plane not directed towards physical material. During the observation sessions, mirrors were placed under the floor of the experimental cage to permit observation when the animal was faced away from the observer. Experimenters were always blind to treatments. In accordance with previously reported data, the treatment with antipsychotic drugs did not result in the development of VCMs in all treated rats (Fachinetto et al., 2007a; Kane and Smith, 1982; Shirakawa and Tamminga, 1994). Therefore, in this evaluation we excluded the animals treated with haloperidol that did not develop at least 30 VCMs within the 6 min of testing.

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2.3.4. Role of CB1 receptors in the anandamide-induced decrease in VCMs The role of CB1 receptors in the protective effect of anandamide against haloperidol-induced VCM was investigated by pretreating the animals with the CB1 receptor antagonist, SR141617A (30 μg/2.5 μL) (Lichtman and Martin, 1997). On day 28 (1 day after the evaluation of haloperidol-induced VCMs), the control and haloperidol-injected groups were subdivided into 4 experimental groups totaling 8 groups: control, SR141716A, anandamide, anandamide + SR141716A, haloperidol, haloperidol + SR141716A, haloperidol + anandamide and haloperidol + SR141716A + anandamide groups. There were 4–6 animals per group. The animals received SR141617A (30 μg, i.c.v.) or its vehicle (100 mM PBS buffer, pH = 7.4, i.c.v.) 6 min before anandamide (6 nmol, i.c.v.) or its vehicle (2% ethanol dissolved in PBS buffer, pH = 7.4, i.c.v.).

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seems to be of particular interest for the identification and development of therapeutic targets in basal ganglia dyskinesias. Accumulating evidence supports a role for the endocannabinoid system as a modulator of dopaminergic activity in the basal ganglia (Fitzgerald et al., 2012; Murillo-Rodríguez et al., 2011; Sañudo-Peña and Walker, 1998; Sañudo-Peña et al., 1996). Therefore, this system's modulation may constitute an important component in new therapeutic approaches for the treatment of motor disorders (Dowie et al., 2010; García-Arencibia et al., 2007; Giuffrida et al., 1999; Glass et al., 2004; Segovia et al., 2003; van der Stelt et al., 2005). The endocannabinoid system consists of signaling lipids and their target receptors. In this context, anandamide (N-arachidonoylethanolamine), which belongs to a class of eicosanoids, has gained attention in the literature as a neurotransmitter within this system (Self, 1999). Two types of cannabinoid receptors have been identified to date. These receptors are the CB1 receptor, cloned in 1990, and the CB2 receptor, cloned in 1993, both of which are members of the superfamily of G-protein-coupled receptors (Mackie, 2005; Matsuda et al., 1990; Munro et al., 1993; Piomelli et al., 2000). The CB1 receptor is expressed throughout the brain, and it is most prevalent in the hippocampus, striatum, cerebellum and cortex, which are structures that regulate learning, movement and cognition, among other behaviors (Svíženská et al., 2008). The majority of the striatal CB1 receptors are located presynaptically on inhibitory GABAergic terminals, modulating neurotransmitter release and influencing the activity of dopaminergic neurons in the substantia nigra (Julian et al., 2003). CB1 and dopamine receptors are co-expressed in striatal neurons, and the activation of the postsynaptic dopamine receptors by dopamine may influence, by different signaling pathways, the functionality and/or expression of CB1 receptors in striatal neurons. Moreover, D2 receptor activation stimulates anandamide release, and the dopamine modulation in the striatum is modified by endocannabinoids, most likely due to its retrograde signaling function (Andre et al., 2010; Giuffrida et al., 1999). Recently, cannabinoid agents have been proposed as promising tools for treating parkinsonism in rats via CB1-mediated mechanisms (Ferrer et al., 2003; Martinez et al., 2012; Morgese et al., 2007). Of particular importance to our study, the lack of cannabinoid CB1 receptors has been demonstrated to increase the severity of motor impairment and dopamine lesions, suggesting that activation of CB1 receptors reduces against the development of L-DOPA-induced dyskinesias (Pérez-Rial et al., 2011). Considering that the activation or blockage of D2 receptors may alter the release of anandamide, our study aimed to investigate whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats.

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Please cite this article as: Röpke J, et al, Anandamide attenuates haloperidol-induced vacuous chewing movements in rats, Prog NeuroPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2014.04.006

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2.4. Statistical analyses

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The data were analyzed using the unpaired t test and one-way or three-way ANOVA followed by Bonferroni's post hoc test. Data were considered significant when p is b0.05.

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3.1. Dose–response curve of anandamide on spontaneous locomotor activity in rats

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Fig. 2 shows that anandamide increased the number of crossings in the open field test at doses of 9 and 27 nmol/site (F(5,17) = 8.172;

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3.2. Effects of i.c.v. administration of a CB1 antagonist (SR141716A) in rats 210 As previously described, haloperidol-treatment caused a marked increase in VCMs compared with its vehicle (p b 0.0001; Fig. 3A). Statistical analysis (three-way ANOVA) revealed a significant interaction between treatment with the antipsychotic (vehicle or haloperidol) and the cannabinoid agonist (vehicle or anandamide) or the cannabinoid antagonist (vehicle or SR141716A): F(1,26) = 8.52; p b 0.005, indicating that SR141716A prevented the effects of anandamide on haloperidol-induced VCMs (Fig. 3B).

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p b 0.01). However, the i.c.v. administration of anandamide at doses of 1, 3 and 6 nmol/site did not alter the number of crossings in the open field test in rats. Because the 6 nmol/site dose was the highest that did not affect locomotion, it was selected for further study.

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Fig. 1. Experimental design. On day 1, the animals received a single administration of either vehicle or haloperidol (38 mg/kg, i.m.). Twenty-four days later, the animals were subjected to stereotaxic surgery to insert a cannula into the lateral ventricle. Three days after surgery (on day 27), the number of VCMs in a six-minute period was evaluated. Animals that did not develop at least 30 VCMs within the 6 min of the test were excluded from the experiment. On day 28, the control and haloperidol-injected groups were subdivided into four experimental groups totaling eight groups: control, SR141716A, anandamide, anandamide + SR141716A, haloperidol, haloperidol + SR141716A, haloperidol + anandamide and haloperidol + SR141716A + anandamide groups. The animals received SR141617A (30 μg, i.c.v.) or its vehicle 6 min before anandamide (6 nmol, i.c.v.) or its vehicle. Afterwards, the rats were placed in cages to quantify VCMs during a 6 minute period.

Fig. 2. Dose–response curve of i.c.v. administration of anandamide on spontaneous locomotor activity in rats (n = 3). * represents significant differences from control group.

Fig. 3. SR141716A and/or anandamide effects on number of VCMs induced by haloperidol in rats. (A) Number of VCMs on the 27th day after haloperidol administration. (B) Number Q2 of VCMs after anandamide (6 nmol, i.c.v)/vehicle (i.c.v.) and/or SR141716A (30 μg, i.c.v.)/ vehicle (i.c.v.) administration on the 28th day after haloperidol administration (n = 4–6). *p b 0.05 compared with respective vehicle group and #p b 0.05 compared with haloperidol-anandamide-SR141716A group by Bonferroni's test. Q3

Please cite this article as: Röpke J, et al, Anandamide attenuates haloperidol-induced vacuous chewing movements in rats, Prog NeuroPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2014.04.006

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TD is a serious side effect caused by treatment with antipsychotic drugs. Particularly, it is problematic due to its high prevalence and the lack of knowledge regarding the causative mechanism of TD. In rodents, VCMs are the primary involuntary orofacial movements observed after antipsychotic exposure, which characterizes TD. Our current results point to a new mechanism for the development of VCMs in rats that involves CB1 receptors. The mechanisms and possible approaches to the management of TD have been studied by different researchers throughout the last decades (Andreassen and Jørgensen, 2000; Apud et al., 2003; Egan et al., 1997; Rizos et al., 2010). However, it is difficult to establish an efficacious treatment without understanding the mechanisms that lead to the development of TD. Different hypotheses have been proposed to explain TD, including the disturbed balance between the dopaminergic and cholinergic systems, the dysfunction of nigrostriatal GABAergic neurons, excitotoxicity, hyperproduction of free radicals due to MAO metabolism and the classical hypothesis related to an increase in dopaminergic sensitivity (Andreassen and Jørgensen, 2000; Cadet et al., 1987; Lohr, 1991; Lohr et al., 2003). All of these hypotheses present inconsistencies; however, the authors are in agreement that the striatonigral dopaminergic pathway is involved in the pathogenesis of TD (Andreassen et al., 1998, 2003; Lohr, 1991; Lohr et al., 2003; Saldaña et al., 2006; Yonder et al., 2004). Accordingly, our group demonstrated that animals with a high frequency of VCM in response to haloperidol or fluphenazine treatment present a decrease in dopamine uptake in the striatum (Fachinetto et al., 2007a, 2007b). Furthermore, molecules which act on specific dopaminergic targets, such as resveratrol, seem to be promising in their ability to avoid antipsychotic-induced VCMs in rats (Busanello et al., 2012). Of particular importance is a recent study in humans, which demonstrated that patients with TD have decreased dopamine transporter expression in the striatum, pointing to the role of the dopaminergic system in the development of involuntary movements (Rizos et al., 2010). Therefore, the mechanisms which could alter dopamine release in the basal ganglia deserve our special attention. Literature has previously shown the regulatory role of endocannabinoids on dopamine function (Beltramo et al., 2000; Gerdeman et al., 2002; Giuffrida et al., 1999; Köfalvi et al., 2005). In 1999, Giuffrida demonstrated that in freely moving rats, dopamine release is accompanied by the release of anandamide in the dorsal striatum, which can act in turn to counter dopamine stimulation of motor activity (Giuffrida et al., 1999). Furthermore, the opposite effects of anandamide in dopamine-mediated motor response have demonstrated that when anandamide levels were increased by inhibiting its transport, the result was hypokinesia that was reversed by the administration of SR141716A and when CB1 agonists and D2 family agonists were administered by local injection into individual basal ganglia nuclei (Beltramo et al., 2000; Sañudo-Peña and Walker, 1998; Sañudo-Peña et al., 1996). Because it is described in the literature that CB1 agonism produces a number of undesirable side effects including catalepsy, locomotor and cognitive impairments, as well as abuse liability (Adams et al., 1998; Di Marzo et al., 2000a, 2000b; Long et al., 2009; Pamplona et al., 2010), we performed a dose–response curve of this endocannabinoid to determine a dose that does not alter locomotion in rats (Giuffrida et al., 1999; Sañudo-Peña and Walker, 1998; Sañudo-Peña et al., 1996; Self, 1999). The maximal dose tested that did not affect spontaneous locomotion was 6 nmol, which was therefore the dose used in the experiments. Considering the interactions between cannabinoids and the dopaminergic system (Dowie et al., 2010; García-Arencibia et al., 2007; Giuffrida et al., 1999; Glass et al., 2004; Segovia et al., 2003; van der Stelt et al., 2005), the present study evaluated the participation of the CB1 receptor in VCMs induced by anandamide in rats. Haloperidol caused a marked increase in VCMs, confirming our previous report

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In conclusion, we demonstrated that VCMs induced by acute treatment with haloperidol may be attenuated by anandamide. Furthermore, the effect of anandamide was blocked by a CB1 receptor antagonist, which suggests that its effect is mediated by CB1 activation. Our results suggest a role for anandamide in the development of orofacial dyskinesia induced by haloperidol in rats.

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(Fachinetto et al., 2007a). The i.c.v. administration of anandamide decreases VCMs in rats. This effect of anandamide is reversed by the previous administration of SR141716A. These results reinforce the participation of CB1 receptors in VCMs induced by haloperidol in rats. Our study shows for the first time that anandamide is able to attenuate VCMs induced by haloperidol in rats. Moreover, the basal ganglia, the main brain area that regulates motor behavior, express a high density of CB1 receptors and has elevated concentrations of endocannabinoids (Di Marzo et al., 2000a, 2000b; Mailleux and Vanderhaeghen, 1992; Tsou et al., 1998). Although CB1 receptors are co-expressed with D1 and D2 dopamine receptors in the striatum and their interactions are still far from being completely understood, it is known that CB1 and D2 receptors are coupled to Gαi/o (Glass and Felder, 1997). However, chronic activation of D2 receptors in striatal primary neuronal culture promotes the functional CB1 coupling to the protein Gαs, which results in increased levels of cAMP (Jarrahian et al., 2004). Furthermore, anandamide, as a retrograde neurotransmitter, can act by controlling the release of dopamine. After chronic exposure to a dopamine antagonist, such as an antipsychotic, this regulatory effect could be changed and could lead to the development of VCMs.

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This work was supported by the PRONEM #11/2029-1, PRONEX/ FAPERGS and INCT–CNPq for excitotoxicity and neuroprotection. C.F.M. and J.F. received a fellowship from CNPq. J.R.R., E.M.R. and A.B. are recipients of a fellowship from CAPES. C.Q.L. received a fellowship from CNPq, and C.M.F. received a fellowship from FAPERGS.

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Please cite this article as: Röpke J, et al, Anandamide attenuates haloperidol-induced vacuous chewing movements in rats, Prog NeuroPsychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2014.04.006

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