Modelling determinants of region-specific dopamine dynamics in the striatum

Abstract

AbstractStriatal dopamine (DA) release regulates reward-related learning, motivation, and behavioural activation, and is believed to consist of a short-livedphasicand continuoustoniccomponent. Here, we build a large-scale three-dimensional model of extracellular DA dynamics in the dorsal (DS) and ventral striatum (VS) based on experimentally determined biological parameters. The model predicts rapid dynamics in DS with little-to-no basal DA, whereas lower uptake capacity in VS slows signalling and enables build-up of atonicDA level. Receptor binding simulations reveal that DA D1 receptor occupancy follows extracellular DA concentration with millisecond delay, while DA D2 receptors integrate DA signal over seconds. The modelling further predicts that VS extracellular levels are highly sensitive to DA transporter (DAT) uptake capacity and posit prevalent nanoclustering of DAT in VS as a regulator of DA uptake. Our simulations substantiate regional differences in extracellular DA dynamics and challenge prevailing paradigms of striatal DA signalling.