Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Abstract

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.

Dopamine-independent state inference mediates expert reward guided decision making

“…However, in both cases, the reinforcing effect of natural rewards was unaffected by inhibiting dopamine neurons, inconsistent with dopaminergic RPEs mediating reward effects, but consistent with the inference-based account above. Similarly, pharmacological manipulation of dopamine signalling in reward guided decision tasks often has limited or no effect on learning 12,[36][37][38] , suggesting dopamine independent influence of rewards on policy. This does not imply dopamine is not involved in such tasks.…”

“…This does not imply dopamine is not involved in such tasks. Pharmacological dopamine manipulations show effects on choice consistency and task engagement even where they show limited or no effect on trial-by-trial learning [37][38][39] . Dopaminergic RPEs likely also drive value learning during initial task acquisition.…”

Cortical dopamine reduces the impact of motivational biases governing automated behaviour

“…A recent study in rodents directly compared effects of dopamine transporter (DAT) blockade, with DAT putatively forming the primary mechanism of striatal dopamine clearance, with COMT inhibition. In this study DAT blockade selectively impaired, and COMT inhibition improved performance after reward reversals 57 . This finding is particularly noteworthy given the opposite effects of two interventions that both increase dopamine, yet presumably in different locations, namely the striatum and prefrontal cortex respectively.…”

“…Stimulation of the meso-cortical dopamine pathway in this study also provides a clue as to the kind of cognitive effects we may expect to see from COMT inhibition both in this study as well as in the clinical domain. Especially noteworthy is that COMT inhibition did not affect fast ventral-tegmental-evoked dopamine transients in the PFC 57 , despite well-known associations between COMT activity and dopamine levels recorded over longer timescales by microdialysis 25 The observation that COMT inhibition may affect dopamine on longer rather than shorter timescales can provide a biological level understanding of the observation in the current study that COMT inhibition through tolcapone affected the overall tendency of biased responding, rather than fast, trial-specific adaptive modulation. This effect could be of particular clinical relevance for disorders characterized by an excessive reliance of automated and habitual responding, as this generalized effect might not only modulate biased responding as reported here, but potentially also affect reliance on habits, i.e.…”

pyControl: Open source, Python based, hardware and software for controlling behavioural neuroscience experiments

“…Task and hardware definition files for these experiments are provided in the manuscripts data repository. For additional use cases see the following studies (Korn et al, 2019;Akam et al, 2020;Koralek and Costa, 2020;Nelson et al, 2020).…”