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 ¼ 44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n ¼ 31) and wild-type (n ¼ 28) mice) and acute (C57BL/6J mice (n ¼ 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 highreward 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.

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

“…The similarity of task designs enables the assessment of mechanisms that might underlie abnormal decision-making in psychiatric patients. We have previously shown that patients with bipolar mania (BD) exhibit poor learning in the task compared with healthy subjects (HC; van Enkhuizen et al, 2014), consistent with other studies (C). Using these strategy assessment measures, it was clear that patients with BD preferred high reward sides after being given low rewards since they are less-likely to repeat preferences for low -but do so for high-rewards.…”

“…The IGT decks are stacked so that selecting from the high reward but higher punishment ("risky") sides result in overall loss over the 100 trials, whereas selecting from the low reward but lower punishment ("safe") sides result in overall gains. While performing the IGT, subjects tend to initially select the risky decks but rapidly (often by trial 20) switch to selecting from the safe decks, although there is a great deal of variability between subjects (Steingroever et al, 2013;van Enkhuizen et al, 2014). The IGT can be extremely useful when assessing the ability of subjects to withhold responding directed toward highly rewarding stimuli in order to obtain even greater gains in the future.…”

“…People with bipolar disorder also exhibit IGT deficits during periods of mania (Clark et al, 2001;Adida et al, 2008;van Enkhuizen et al, 2014) and euthymia and depression (Adida et al, 2011). Although IGT deficits in bipolar patients with euthymia were not always replicated with smaller sample sizes (Edge et al, 2013), it is clear that during mania, patients exhibited poor IGT performance (van Enkhuizen et al, 2014).…”

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…Lower DAT functioning has been related to a hyperdopaminergic state and higher DAT to a lower dopaminergic activity (Laasonen-Balk et al, 1999;Van Enkhuizen et al, 2014). However, without optimal clearance due to lower DAT affinity or expression, DA release more readily diffuses into extrasynaptic space where it can also provide strong feedback inhibition and dampen DA turnover and thus the final outcome is likely dependent on modulatory variables such as D2S sensitivity (Dickinson et al, 1999;Jones et al, 1999).…”

Translational Rodent Paradigms to Investigate Neuromechanisms Underlying Behaviors Relevant to Amotivation and Altered Reward Processing in Schizophrenia

“…This task has since been adapted for use in both rats 68,69 and mice. 65 Unlike the probabilistic learning task however, the IGT utilizes more punishment and risk during task learning and so incorporates even more aspects of cognition that could confound behavioral results. Hence, making choices in this task based on feedback may provide a window into reward anticipation that links to motivation in patients with schizophrenia.…”