UNCORRECTED PROOF 1 Anandamide attenuates haloperidol-induced vacuous chewing 2 movements in rats 3 Jivago Q1 Röpke a , Alcindo Busanello a , Caroline Queiroz Leal c , Elizete de Moraes Reis a , Catiuscia Molz de Freitas c , 4 Jardel Gomes Villarinho a , Fernanda Hernandes Figueira b , Carlos Fernando Mello a , 5 Juliano Ferreira a,b , Roselei Fachinetto a,b, ⁎ 6 a Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil 7 b Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria, RS, Brazil 8 c Curso de Farmácia, Universidade Federal de Santa Maria, RS, Brazil abstract 9 article info 10 Article history: 11 Received 9 October 2013 12 Received in revised form 26 March 2014 13 Accepted 9 April 2014 14 Available online xxxx 15 Keywords: 16 Anandamide 17 Dopaminergic system 18 Endocannabinoids 19 Open field 20 Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the 21 dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their 22 underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal 23 ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders 24 has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol- 25 induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate 26 (38 mg/kg, intramuscularly — i.m.). The effect of anandamide (6 nmol, intracerebroventricularly — i.c.v.) and/or 27 the CB1 receptor antagonist SR141716A (30 μg, i.c.v.) on haloperidol-induced vacuous chewing movements 28 (VCMs) was assessed 28 days after the start of the haloperidol treatment. Anandamide reversed haloperidol- 29 induced VCMs; SR141716A (30 μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect 30 of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs 31 in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia. 32 © 2014 Published by Elsevier Inc. 33 34 35 36 37 1. Introduction 38 Antipsychotics are a class of drugs used for the treatment of psychi- 39 atric disorders. Current pharmacological evidence suggests that dopa- 40 mine D2 receptor antagonism on the mesolimbic pathway is a major 41 determinant of antipsychotic action (Seeman, 1987). However, anti- 42 psychotics also antagonize striatal dopamine D2 receptors in the 43 nigrostriatal dopaminergic pathway, which have been implicated in 44 the development of acute and chronic involuntary motor effects, of 45 which tardive dyskinesia (TD) is the most severe (Crane, 1968; Creese 46 et al., 1976; Kane, 1995; Tarsy and Baldessarini, 1977). TD is a syndrome 47 characterized by involuntary orofacial movements, which can also affect 48 the musculature of the trunk and upper and lower limbs (Egan et al., 49 1996). This syndrome has clinical relevance due to its high prevalence 50 in humans treated with antipsychotic medications, as well as its persis- 51 tence and irreversibility, even after treatment withdrawal (Casey, 1985; 52 Crane, 1973; Jeste et al., 1979). Despite the large number of studies, the 53 pathophysiological mechanisms of TD remain unclear, which hinders 54 the discovery of an effective treatment. Several hypotheses have 55 been proposed to explain the development of TD (Andreassen and 56 Jørgensen, 2000). The classical hypothesis to explain TD is the develop- 57 ment of dopaminergic supersensitivity, which can result from the 58 chronic use of antipsychotics (Burt et al., 1977; Klawans and Rubovits, 59 1972; Rubinstein et al., 1990). Accordingly, the chronic blockage of do- 60 pamine receptors by D2 antagonists increases the number of receptors 61 and the sensitivity of the dopaminergic receptors, culminating in a 62 hyperdopaminergic state, which could be responsible for TD (Cavallaro 63 and Smeraldi, 1995; Kane, 1995). However, there are inconsistencies 64 in this hypothesis, and other alterations in the dopaminergic system 65 have been reported. It was previously demonstrated that orofacial 66 dyskinesia (OD), a syndrome caused by antipsychotics in rodents with 67 similar characteristics to TD in humans, is related to a decrease in dopa- 68 mine uptake in the striatum of rats treated with antipsychotics, either 69 haloperidol or fluphenazine (Fachinetto et al., 2007a, 2007b). Accord- 70 ingly, a decreased density of dopamine transporters in patients with 71 TD has recently been reported (Rizos et al., 2010). Therefore, the eluci- 72 dation of the regulatory mechanisms of striatal dopaminergic activity Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2014) xxx–xxx Abbreviations: ANOVA, analysis of variance; CB1, cannabinoid receptor 1; D2, dopa- mine 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. Q4 Tel.: +55 3220 8096x21; fax: +55 3220 8241x21. E-mail address: roseleirf@gmail.com.br (R. Fachinetto). PNP-08592; No of Pages 5 http://dx.doi.org/10.1016/j.pnpbp.2014.04.006 0278-5846/© 2014 Published by Elsevier Inc. Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp Please cite this article as: Röpke J, et al, Anandamide attenuates haloperidol-induced vacuous chewing movements in rats, Prog Neuro- Psychopharmacol Biol Psychiatry (2014), http://dx.doi.org/10.1016/j.pnpbp.2014.04.006