Mechanisms for regulation of dopamine transmission are critical to its effects on behavior and vary by region. Recycling via the dopamine transporter (DAT) predominates in striatum, while degradation by catechol-O-methyltransferase (COMT) predominates in cortex. However, questions remain about whether and how each mechanism affects fast fluctuations in dopamine transmission in these regions and influences behavior. To address this issue, we used pharmacological blockade of each clearance mechanism to assess their roles in reward-guided decision making and in regulating sub-second dopamine transmission in striatum and cortex.We found that DAT and COMT selectively influence reward value updating in opposite directions, with DAT blockade impairing and COMT inhibition improving learning in a multi-step decision making task that requires mice to monitor changes in both optimal response strategy and reward probabilities. By contrast, neither drug influenced the speed of reversals following a change in action-state transition probabilities. In addition, DAT but not COMT influenced task engagement and motivation to work for reward in both the decision making task and a progressive ratio paradigm. Fast scan cyclic voltammetry recordings of evoked dopamine release in anesthetized mice revealed that DAT but not COMT blockade enhanced dopamine transients in nucleus accumbens. Unexpectedly, neither manipulation had an effect on evoked release in medial frontal cortex. Together, these data refine our understanding of how dopamine clearance mechanisms operate in different regions and at distinct timescales to shape aspects of reward-guided decision making.
3
Significance StatementDopamine transmission is tightly regulated by clearance mechanisms and these clearance mechanisms exhibit regional specificity. However, while we know a lot about how the activity of dopamine neurons relates to reward-guided behavior, the precise role of different clearance mechanisms in shaping these processes is much less understood. This is important, as dysfunctional clearance mechanisms have been implicated in many neuropsychiatric disorders.Here, we show specific and distinct roles for two clearance mechanisms -the dopamine transporter and catechol-O-methyltransferase -in reward value, but not action-state probability, updating during multi-step decision making, and in regulating striatal and cortical dopamine transients. Our findings demonstrate how regulation of dopamine transmission, over distinct timescales and in different brain regions, can influence multiple aspects of reward-guided behavior.