B vitamins attenuate haloperidol-induced orofacial dyskinesia in rats: possible involvement of antioxidant mechanisms Danielle Silveira Mace ˆdo a , Gersilene Valente de Oliveira a , Patrı ´cia Xavier Lima Gomes a , Fernanda Yvelize Ramos de Arau ´jo a , Carolina Melo de Souza a , Silva ˆnia Maria Mendes Vasconcelos a , Glauce Socorro de Barros Viana a , Francisca Cle ´ a Florenc ¸o de Sousa a and Andre ´ Fe ´ rrer Carvalho b Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose pathophysiology is associated to oxidative stress. Treatments that maintain antipsychotic efficacy while reducing TD risk are awaited. Haloperidol (HAL), a typical antipsychotic, is used as a putative murine model of TD. Here, we evaluated the protective role of vitamins B1, B6, and B12 alone or in combination (vitamin B cocktail) in preventing the HAL-induced orofacial dyskinesia (OD), based on their antioxidant properties. HAL (1 mg/kg) administered intraperitoneally to Wistar rats for 21 days caused OD and increased catalepsy time. The daily administration of vitamins B (B1 : B6 : B12 at 60 : 60 : 0.6 mg/kg) alone or the vitamin B cocktail, along with HAL, prevented the development of OD. Catalepsy time reduced in all groups treated with vitamins B, but to a lesser extent than OD. The participation of oxidative stress was assessed by the determination of reduced glutathione (GSH) levels and lipid peroxide formation in the striatum. HAL significantly decreased GSH levels and enhanced lipid peroxidation, whereas B1, B12, and vitamin B cocktail prevented the decrease in GSH levels. All groups treated with vitamins B presented a decrease in lipid peroxide formation. The data suggest a promising role for vitamins B in the prevention of OD. Behavioural Pharmacology 00:000–000  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2011, 00:000–000 Keywords: haloperidol, orofacial dyskinesia, oxidative stress, rat, striatum, tardive dyskinesia a Departments of Physiology and Pharmacology and b Clinical Medicine, Federal University of Ceara ´ , Fortaleza, Ceara ´ , Brazil Correspondence to Professor Danielle Silveira Mace ˆ do, PhD, Department of Physiology and Pharmacology, Federal University of Ceara ´ , Rua Cel. Nunes de Melo 1127, Fortaleza 60431-270, CE, Brazil E-mail: daniellesm2000@yahoo.com Received 7 February 2011 Accepted as revised 26 May 2011 Introduction Treatment with typical antipsychotic drugs is associated with a wide range of extrapyramidal side-effects (EPS) such as parkinsonism and orofacial dyskinesia (OD) in up to 20–40% of schizophrenic patients treated with such drugs (Latimer, 1995; Hoff et al., 1999; Kane, 2001). OD is an iatrogenic syndrome characterized by repetitive, stereotyped, and choreoathetoid movements of the oro-buccal–lingual–facial musculature, although other parts of the body may also be affected, such as limbs and trunk (Kane et al., 1988). Current evidence supports a lower risk of OD for second-generation antipsychotic drugs (atypical) (Margolese et al., 2005; Correll and Schenk, 2008). However, OD remains a significant adverse outcome in the era of atypical antipsychotic drugs (Woods et al., 2010). Mechanisms for OD development include prolonged blockade of postsynaptic dopamine receptors, postsynap- tic dopamine receptor hypersensitivity, and damage to both g-aminobutyric acid (GABA) and cholinergic striatal interneurons (Margolese et al., 2005). An in- crease in the generation of free radicals as a result of dopamine metabolism has also been proposed as a putative pathophysiological mechanism for OD (Naidu and Kulkarni, 2001). OD and other related movement disorders that develop after treatment with antipsychotic drugs involve neuronal cell death. Cell death may encompass the activation of a variety of death-execution macromolecules (Mitchell et al., 2002; Rogoza et al., 2004). Among the multitude of signal pathways that are triggered in typical anti- psychotic drug-induced EPS, the mitochondria-mediated apoptotic pathways are considered to be a fundamental component of cell death (Mitchell et al., 2002; Qing et al., 2003; Rogoza et al., 2004). Following protracted haloper- idol (HAL) administration, a number of damaging stimuli, such as (a) striatal production of quinones and hydrogen peroxide (H 2 O 2 ) in the basal ganglia due to increased dopamine turnover and (b) high concentrations of proapoptotic molecules (e.g. Bid and Bax) may activate mitochondrial death pathways through the release of soluble intermembrane proteins (Ukai et al., 2004). In fact, increased levels of lipid peroxidation products in the blood and cerebrospinal fluid of OD patients have Original article 1 0955-8810  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32834aff6d CE: Satish ED: Asra Op: Sampath FBP 200559: LWW_FBP_200559