The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatalD1andD2dopaminereceptortypeshasbeenarguedtoconstraintheD1andD2signalingpathwaystophasicandtonicdopaminesignals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorallyrelevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling.

The neuromodulator dopamine plays a key role in motivation, reward-related learning and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signalling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, due to slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signalling. Significance statementCurrent models of basal ganglia function are often based on a distinction of two types of 1 dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic 2 dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic 3 dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view 4 does not take into account the rates for the binding and unbinding of dopamine to D1 and 5 D2 receptors. By incorporating these kinetics into a computational model we show that D1 6 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications 7 for the processing of reward-related and motivational signals in the basal ganglia. 8 35 1989) leading to ≈ 40% of D2Rs being occupied at a baseline [DA] of 20nM . Due to their high 36 affinity, D2Rs can detect low amplitude, tonic increases/decreases in [DA]. However, as D2Rs 37 saturate at relatively low [DA] > 2 · K D2 D , and are therefore unable to detect high amplitude, 38 phasic increases in [DA]. This suggests that D1 and D2 type MSNs respond differently to 39 2 Hunger et al. Dopamine receptor abundance compensates kinetics phasic and tonic changes in [DA], solely because of the different affinities of D1Rs and D2Rs 40 (Schultz, 2007). However, this model neglects other factors relevant for receptor occupation 41 and is also incompatible with recent findings that D2R expressing MSNs can detect phasic 42 changes in [DA] (Marcott et al., 2014; Yapo et al., 2017). 43The affinity-based model assumes that the reaction equilibrium is reached instantaneously, 44 whereby the receptor binding affinity can be used to approximate the fraction of r...