Locomotor activity depends on β-arrestin recruitment by the dopamine D receptor in the striatal D-D receptor heteromer.

Several dopaminergic compounds, including the clinically used pramipexole, are labelled as preferential dopamine D receptor (DR) agonists based on their moderately higher affinity for the DR versus other D-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 DRs and postsynaptic striatal DRs, 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 DR agonists. Their differential properties reveal that their locomotor activating effects in mice are dependent on the striatal postsynaptic DRs forming heteromers with DRs, via their ability to potentiate β-arrestin recruitment by the DR in the DR-DR heteromer. The results also indicate that the locomotor depressant effects are largely dependent on their ability to activate presynaptic DRs. More broadly, it is demonstrated that locomotor activity in mice depends on β-arrestin recruitment by the DR in the striatal DR-DR heteromer. These results can have implications for the treatment of L-dopa-induced dyskinesia and Restless Legs Syndrome.