title: GBR 12909 administration as an animal model of bipolar mania: time course of behavioral, brain oxidative alterations and effect of mood stabilizing drugs.
abstract: Polymorphisms in the human dopamine transporter (DAT) are associated with bipolar endophenotype. Based on this, the acute inhibition of DAT using GBR12909 causes behavioral alterations that are prevented by valproate (VAL), being related to a mania-like model. Herein our first aim was to analyze behavioral and brain oxidative alterations during a 24 h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2 h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24 h post-administration. Hyperlocomotion, levels of reduced glutathione (GSH) and lipid peroxidation in brain areas were assessed at all these time-points. GBR12909 caused hyperlocomotion at 2 and 24 h. Rearing behavior increased only at 2 h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12 h. Increased lipid peroxidation was detected at the time-points of 2 and 12 h in all brain areas studied. At the time-point of 2 h post-GBR12909 Li prevented the hyperlocomotion and rearing alterations, while VAL prevented only rearing alterations. Both drugs prevented pro-oxidative changes. In conclusion, we observed that the main behavioral and oxidative alterations took place at the time-period of 2 h post-GBR12909, what points to this time-period as the best for the assessment of alterations in this model. Furthermore, the present study expands the predictive validity of the model by the determination of the preventive effects of Li.
authors.affiliation: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Ana Isabelle G
authors.initials: AI
authors.lastname: Queiroz
authors.forename: Maíra Moraes
authors.initials: MM
authors.lastname: de Araújo
authors.forename: Tatiane
authors.initials: T
authors.lastname: da Silva Araújo
authors.forename: Greicy Coelho
authors.initials: GC
authors.lastname: de Souza
authors.forename: Lígia Menezes
authors.initials: LM
authors.lastname: Cavalcante
authors.forename: Michel
authors.initials: M
authors.lastname: de Jesus Souza Machado
authors.forename: David Freitas
authors.initials: DF
authors.lastname: de Lucena
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.forename: Danielle
authors.initials: D
authors.lastname: Macêdo
mesh_terms: D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018692:Antimanic Agents; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine