Locomotor activity depends on β-arrestin recruitment by the dopamine D₁ receptor in the striatal D1-D3 receptor heteromer

Several dopaminergic compounds, including the clinically used pramipexole, are labelled as preferential dopamine D₃ receptor (D₃R) agonists based on their moderately higher affinity for the D₃R versus other D₂-like receptor subtypes. In rodents, these compounds typically produce locomotor depression with low doses and locomotor activation with higher doses, which has been assumed to be mediated by presynaptic D₃Rs and postsynaptic striatal D₂Rs, respectively. However, studies with selective pharmacological and genetic blockade of each dopamine receptor subtype suggest opposite roles. We address this apparent conundrum by performing a comprehensive in vitro, in vivo and ex vivo pharmacological comparison of several preferential D₃R agonists. Their differential properties reveal that their locomotor activating effects in mice are dependent on the striatal postsynaptic D₃Rs forming heteromers with D₁Rs, via their ability to potentiate β-arrestin recruitment by the D₁R in the D₁R-D₃R heteromer. The results also indicate that the locomotor depressant effects are largely dependent on their ability to activate presynaptic D₂Rs. More broadly, it is demonstrated that locomotor activity in mice depends on β-arrestin recruitment by the D₁R in the striatal D₁R-D₃R heteromer. These results can have implications for the treatment of L-dopa-induced dyskinesia and Restless Legs Syndrome.