title: Adolescent GBR12909 exposure induces oxidative stress, disrupts parvalbumin-positive interneurons, and leads to hyperactivity and impulsivity in adult mice.
abstract: The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress. The current study sought to model this adolescent neurochemical "stress" by exposing mice to the dopamine transporter inhibitor GBR12909 (5mg/kg; IP) during adolescence (postnatal day 35-44) and measuring the resultant effect on locomotor behavior and probabilistic reversal learning as well as GABAergic interneurons and oxidative stress in adulthood. C57BL6/J mice exposed to GBR12909 showed increased activity in a novel environment and increased impulsivity as measured by premature responding in the probabilistic reversal learning task. Adolescent GBR12909-exposed mice also showed decreased parvalbumin (PV) immunoreactivity in the prefrontal cortex, which was accompanied by increased oxidative stress in PV+ neurons. These findings indicate that adolescent exposure to a dopamine transporter inhibitor results in loss of PV in GABAergic interneurons, elevations in markers of oxidative stress, and alterations in behavior in adulthood.
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
authors.forename: Asma
authors.initials: A
authors.lastname: Khan
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Loek A W
authors.initials: LA
authors.lastname: de Jong
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Kamenski
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Kerin K
authors.initials: KK
authors.lastname: Higa
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, CA, United States.
authors.forename: Jacinta D
authors.initials: JD
authors.lastname: Lucero
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, CA, United States. Electronic address: mbehrens@salk.edu.
authors.forename: M Margarita
authors.initials: MM
authors.lastname: Behrens
authors.affiliation: Dept of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States. Electronic address: sbpowell@ucsd.edu.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
mesh_terms: D000818:Animals; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006948:Hyperkinesis / Q000378:metabolism / Q000473:pathology; D007175:Impulsive Behavior / Q000187:drug effects* / Q000502:physiology; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D011337:Probability Learning; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology
chemical_list: D010320:Parvalbumins; D010879:Piperazines; C043425:vanoxerine
keywords: GBR 12909; adolescence; impulsivity; mice; oxidative stress; parvalbumin interneurons