title: Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder.
abstract: Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n = 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n = 31) and wild-type (n = 28) mice) and acute (C57BL/6J mice (n = 89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by high-reward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies.
authors.affiliation: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jordy
authors.initials: J
authors.lastname: van Enkhuizen
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Brook L
authors.initials: BL
authors.lastname: Henry
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Arpi
authors.initials: A
authors.lastname: Minassian
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Perry
authors.affiliation: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Morgane
authors.initials: M
authors.lastname: Milienne-Petiot
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Kerin K
authors.initials: KK
authors.lastname: Higa
authors.affiliation: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001714:Bipolar Disorder / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003657:Decision Making / Q000187:drug effects / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D005717:Games, Experimental; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology; D007206:Individuality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D012201:Reward; D012309:Risk-Taking; D055815:Young Adult
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine