title: Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways.
abstract: It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex, hippocampus and striatum. Minocycline and risperidone prevented and reversed ketamine-induced alterations in behavioral paradigms, oxidative markers (i.e. ketamine-induced decrease and increase in GSH levels and TBARS content, respectively) as well as nitrite levels in the striatum. These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitrergic systems.
authors.affiliation: 1Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Aline Santos
authors.initials: AS
authors.lastname: Monte
authors.forename: Greicy Coelho
authors.initials: GC
authors.lastname: de Souza
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Soczynska
authors.forename: Júnia Vieira
authors.initials: JV
authors.lastname: dos Santos
authors.forename: Rafaela Carneiro
authors.initials: RC
authors.lastname: Cordeiro
authors.forename: Bruna Mara Machado
authors.initials: BM
authors.lastname: Ribeiro
authors.forename: David Freitas
authors.initials: DF
authors.lastname: de Lucena
authors.forename: Silvânia Maria Mendes
authors.initials: SM
authors.lastname: Vasconcelos
authors.forename: Francisca Cléa Florenço
authors.initials: FC
authors.lastname: de Sousa
authors.forename: André Férrer
authors.initials: AF
authors.lastname: Carvalho
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Macêdo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000378:metabolism; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine; D008297:Male; D018782:Maze Learning; D051379:Mice; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000032:analysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects; D012919:Social Behavior; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D014150:Antipsychotic Agents; D009573:Nitrites; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D007649:Ketamine; D008911:Minocycline; D005978:Glutathione; D018967:Risperidone
keywords: Minocycline; cognition; ketamine-induced model; prepulse inhibition; schizophrenia; social interaction