Modelling determinants of region-specific dopamine dynamics in the striatum

Striatal dopamine (DA) release regulates reward-related learning and behavioural activation and is believed to consist of a short-lived phasic and continuous tonic component. Here, we build a three-dimensional model of extracellular DA dynamics in dorsal (DS) and ventral striatum (VS) that include tens of thousands of DA release sites. The model predicts rapid dynamics in DS with little-to-no basal DA, and much slower dynamics in the VS enabling build-up of a tonic DA level. These regional differences do not primarily reflect different release phenomena but rather arise from differential dopamine transporter (DAT) activity. Interestingly, our simulations posit prevalent nanoclustering of DAT as a possible regulator of this activity. Receptor binding simulations show that D1 receptor occupancy follows extracellular DA concentration with millisecond delay, while D2 receptors integrate DA signal over seconds. Summarized, our model distills recent experimental observations into a computational framework that challenge prevailing paradigms of striatal DA signalling.