Vitamin E attenuates reserpine-induced oral dyskinesia and striatal oxidized glutathione/reduced glutathione ratio (GSSG/GSH) enhancement in rats Vanessa C. Abı ´lio a , Carlos C.S. Araujo a , Marcelo Bergamo a , Patricia R.V. Calvente a , Va ˆnia D’Almeida b , Rosana de A. Ribeiro a , Roberto Frussa-Filho a, * a Departamento de Farmacologia, Universidade Federal de Sa ˜o Paulo, Rua Botucatu, 862-Ed. Leal Prado, Sa ˜o Paulo, SP CEP 04023-970, Brazil b Departamento de Pediatria, Universidade Federal de Sa ˜o Paulo, Sa ˜o Paulo, Brazil Accepted 18 November 2002 Abstract The effects of a previous and concomitant treatment with vitamin E (VE) were studied on an animal model of tardive dyskinesia, i.e., the frequency of spontaneous tongue protrusions in rats treated with reserpine (RE). VE (5, 10, 20 or 40 mg/kg administered intraperitoneally, daily, for 19 days) attenuated the increase in tongue protrusion frequency induced by RE (1 mg/kg administered subcutaneously, on Days 16 and 18, 1 h after VE), which was quantified on Day 19. In a second experiment, a similar treatment with 20 mg/kg VE attenuated RE-induced increase in the striatal ratio of oxidized/reduced glutathione (GSSG/GSH), an index of the oxidative stress process. These results support the free radical hypothesis of tardive dyskinesia. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Oxidative stress; Rat; Reserpine; Tardive dyskinesia; Tongue protrusion; Vitamin E 1. Introduction The term tardive dyskinesia encompasses a broad spec- trum of potentially irreversible involuntary hyperkinetic dyskinesias associated with exposure to long-term classical neuroleptic treatment. These late-onset involuntary move- ments, most commonly affecting the orofacial region (i.e., buccolingual-masticatory dyskinesia), represent a major limitation of chronic antipsychotic drug therapy. Indeed, in the therapeutic management of tardive dyskinesia, no drugs have been shown to be both safe and effective over extended periods (Gardos and Cole, 1995). Neisewander et al. (1994) have suggested that reserpine (RE)-induced oral dyskinesia may provide a new animal model of tardive dyskinesia. Indeed, rats treated with this monoamine-depleting agent develop orofacial dyskinesia characterized by tongue protrusion, twitching of the facial musculature and vacuous chewing movements (Neisewan- der et al., 1991a,b, 1994, 1996; Vital et al., 1997; Bergamo et al., 1997; Queiroz et al., 1998; Queiroz and Frussa-Filho, 1999; Calvente et al., 2002; Abı ´lio et al., 2002). In this regard, although RE is not classified as a neuroleptic, it has been used as an antipsychotic agent and has been associated with the development of tardive dyskinesia (Uhrbrand and Faurbye, 1960). This RE-induced orofacial dyskinesia (especially tongue protrusion frequency) in rats has also other features that are consistent with tardive dyskinesia, including persistence following termination of administra- tion and dose-dependent blockade by a dopamine D 2 receptor antagonist (Neisewander et al., 1991a,b). Further- more, whereas at high doses of RE, the response appears within 3 days, at low doses, the response is not evident until many days of treatment (Neisewander et al., 1994), consist- ent with the protracted development of tardive dyskinesia in humans (Gerlach and Casey, 1988). As with tardive dyski- nesia (Wolfarth and Ossowska, 1989), RE-induced oral dyskinesia is exacerbated by dopamine agonists like amphetamine and seems to be mediated, at least in part, 0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(02)00340-8 Abbreviations: GSH, reduced glutathione; GSSG, oxidized glutathione. * Corresponding author. Tel.: +55-11-5549-4122; fax: +55-11-273- 1766. E-mail address: abilio.farm@epm.br (R. Frussa-Filho). www.elsevier.com/locate/pnpbp Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 109– 114