title: Evaluation of behavioral and neurochemical changes induced by ketamine in rats: implications as an animal model of mania.
abstract: Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness characterized by recurrent manic and depressive episodes. Mood stabilizing agents such as lithium and valproate are two primary drugs used to treat BD. To develop a novel animal model of mania (hallmark of BD), it is important to assess the therapeutic and prophylactic effect of these mood stabilizers on the new candidate target animal model. The present work investigates the therapeutic and prophylactic value of lithium and valproate in a novel preclinical animal model of mania, induced by ketamine. In the prevention protocol, wistar rats were pretreated with lithium (47.5 mg/kg, i.p., twice a day), valproate (200 mg/kg, i.p., twice a day), or saline (i.p., twice a day) for 14 days. Between days 8 and 14, the rats were treated with ketamine (25 mg/kg, i.p.) or saline. In the reversal protocol, rats first received ketamine (25 mg/kg, i.p.) or saline. After, the administration of lithium, valproate, or saline was carried out for seven days. Our results indicated that lithium and valproate reversed and prevented ketamine-induced hyperlocomotion. Moreover, lithium and valproate reversed (prefrontal cortex, hippocampus, and striatum) and prevented (prefrontal cortex, hippocampus, striatum, and amygdala) the increase of the TBARS level induced by ketamine. The protein carbonyl formation, induced by ketamine, was reversed by lithium and valproate in the prefrontal cortex, hippocampus, and striatum, and prevented only in the amygdala. These findings support the notion that the administration of ketamine might be a promising pharmacological animal model of mania, which could play a role in the pathophysiology of BD.
authors.affiliation: Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
authors.forename: Fernando V
authors.initials: FV
authors.lastname: Ghedim
authors.forename: Daiane de B
authors.initials: Dde B
authors.lastname: Fraga
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Deroza
authors.forename: Mariana B
authors.initials: MB
authors.lastname: Oliveira
authors.forename: Samira S
authors.initials: SS
authors.lastname: Valvassori
authors.forename: Amanda V
authors.initials: AV
authors.lastname: Steckert
authors.forename: Josiane
authors.initials: J
authors.lastname: Budni
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Zugno
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects*; D001714:Bipolar Disorder / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D007649:Ketamine / Q000008:administration & dosage*; D008094:Lithium / Q000008:administration & dosage; D008297:Male; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D018692:Antimanic Agents; D014635:Valproic Acid; D007649:Ketamine; D008094:Lithium