title: The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania.
abstract: Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses.
  
  
  
  The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography.
  
  
  
  Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels.
  
  
  
  Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Morgane
authors.initials: M
authors.lastname: Milienne-Petiot
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Kesby
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Graves
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Jordy
authors.initials: J
authors.lastname: van Enkhuizen
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Arpi
authors.initials: A
authors.lastname: Minassian
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: jaredyoung@ucsd.edu.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000378:metabolism* / Q000523:psychology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D004334:Drug Administration Schedule; D006719:Homovanillic Acid / Q000378:metabolism; D008094:Lithium / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D011340:Problem Solving / Q000187:drug effects / Q000502:physiology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008094:Lithium; D006719:Homovanillic Acid
keywords: Breakpoint; Cognition; DAT knockdown; GBR12909; HPLC; HVA