title: Alpha-phenyl-N-tert-butylnitrone prevents oxidative stress in a haloperidol-induced animal model of tardive dyskinesia: investigating the behavioural and biochemical changes.
abstract: Haloperidol (HP) is a widely prescribed antipsychotic drug used for the treatment of mental disorders. However, while providing therapeutic benefits, this drug also causes serious extrapyramidal side effects, such as tardive dyskinesia (TD). Upon chronic administration, HP causes behavioural supersensitivity to dopamine D2 receptor agonists, as well as the development of vacuous chewing movements (VCMs), in an animal model of human TD. Currently, a prevailing hypothesis to account for these behavioural abnormalities implicates oxidative stress. This study was undertaken to examine whether the free radical trapping agent, α-phenyl-N-tert-butylnitrone (PBN), can prevent the development of behavioural supersensitivity to dopamine D2 receptor agonists and the development of VCMs. Additionally, the study examined whether increased synthesis of apoptosis inducing factor (AIF) can result from HP-induced oxidative stress. Male Sprague-Dawley rats were treated with HP in conjunction with PBN, or its vehicle, for 4weeks. After a 24-hour washout period, behavioural observations were recorded along with the estimation of lipid peroxidation and antioxidant enzyme activities. The free radical trapping agent, PBN, prevented the development of behavioural supersensitivity, reduced lipid peroxidation and prevented the reduction of antioxidant enzyme activities. AIF concentrations at the mRNA and protein levels remained unchanged; therefore increased AIF gene expression is unlikely to be involved in HP-induced oxidative stress. The findings of the present study suggest the involvement of striatal free radicals in the development of behavioural supersensitivity, and free radical trapping agents, such as PBN, as possible options for the treatment of extrapyramidal side effects in humans.
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. dayarp@mcmaster.ca
authors.forename: Ritesh P
authors.initials: RP
authors.lastname: Daya
authors.forename: Mattea L
authors.initials: ML
authors.lastname: Tan
authors.forename: Christal D
authors.initials: CD
authors.lastname: Sookram
authors.forename: Kevin
authors.initials: K
authors.lastname: Skoblenick
authors.forename: Ram K
authors.initials: RK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; C029217:phenyl-N-tert-butylnitrone; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D006220:Haloperidol