van Enkhuizen Jordy, Henry Brook L, Minassian Arpi, Perry William, Milienne-Petiot Morgane, Higa Kerin K, Geyer Mark A, Young Jared W
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.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Neuropsychopharmacology. 2014 Dec;39(13):3112-22. doi: 10.1038/npp.2014.170. Epub 2014 Jul 9.
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.
双相情感障碍（BD）患者存在有害的决策行为，对他们的生活产生负面影响。这种异常决策可以通过爱荷华赌博任务（IGT）进行量化，该任务要求根据不同的奖励/惩罚时间表在有利和不利选项之间进行选择。这种行为缺陷背后的机制尚不清楚，但可能包括BD患者中报道的多巴胺转运体（DAT）功能降低。我们使用人类和小鼠IGT，测试了DAT功能降低是否会重现BD患者决策缺陷的模式。我们评估了16名BD受试者（7名女性）和17名健康对照（HC）受试者（12名女性）的IGT表现。我们记录了标准的IGT表现指标以及新颖的奖励后和惩罚后决策策略。我们使用C57BL/6J小鼠（n = 44）对一种新颖的单节段小鼠IGT进行了表征。将BD和HC的IGT表现与慢性（基因敲低（KD；n = 31）和野生型（n = 28）小鼠）和急性（用DAT抑制剂GBR12909处理C57BL/6J小鼠（n = 89））降低DAT功能对执行这种新颖IGT的小鼠的影响进行了比较。与HC受试者相比，BD患者表现出决策受损。表现良好的DAT KD小鼠和接受GBR12909治疗的小鼠在小鼠IGT中均表现出决策不良。每个群体的缺陷都是由高奖励敏感性驱动的。单节段小鼠IGT测量的基于动态风险的决策与人类相似。小鼠中DAT功能的慢性和急性降低损害了决策，这与BD患者IGT表现不佳一致。DAT减少引起的多巴胺能亢进可能会影响BD患者的不良决策，这一点应在未来的研究中得到证实。
