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

Hot Off the Press – August, 2025

Published in Pharmacological Research by Alexandra Evans and Sergi Ferré , et al. of the NIDA IRP Integrative Neurobiology Section.

Summary

It has been long advocated that the mechanism responsible for the classically established cooperative effect of dopamine D1-like and D2-like receptor agonists in the elicitation of locomotor activity in rodents is the simultaneous activation of stimulatory D1 receptors (D1Rs) in the direct GABAergic striatal efferent pathway and of inhibitory D2Rs in the indirect efferent pathway. This new study demonstrates instead that such a cooperative effect depends on interactions between D1Rs and D3Rs mediated by D1R-D3R heteromers at the same striatal neuronal level. Even more specifically, it demonstrates that locomotor activity in mice depends on β-arrestin recruitment by the D1R in thestriatal D1R-D3R heteromer. These results can have implications for the treatment of L-dopa-induced dyskinesia and Restless Legs Syndrome.

Publication Information

Evans, Alexandra H; Ciruela-Jardí, Marc; Rea, William; Keegan, Bradley M; Levinstein, Marjorie R; Bonifazi, Alessandro; Cao, Jianjing; Jackson, Shelley N; Shi, Lei; Casajuana-Martin, Nil; Cai, Ning-Sheng; Casadó, Vicent; Earley, Christopher J; Newman, Amy H; Michaelides, Michael; Pardo, Leonardo; Moreno, Estefanía; Ferré, Sergi

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

In: Pharmacol Res, vol. 218, pp. 107826, 2025, ISSN: 1096-1186.

Abstract | Links

@article{pmid40523512,

title = {Locomotor activity depends on β-arrestin recruitment by the dopamine D receptor in the striatal D-D receptor heteromer},

author = {Alexandra H Evans and Marc Ciruela-Jardí and William Rea and Bradley M Keegan and Marjorie R Levinstein and Alessandro Bonifazi and Jianjing Cao and Shelley N Jackson and Lei Shi and Nil Casajuana-Martin and Ning-Sheng Cai and Vicent Casadó and Christopher J Earley and Amy H Newman and Michael Michaelides and Leonardo Pardo and Estefanía Moreno and Sergi Ferré},

url = {https://pubmed.ncbi.nlm.nih.gov/40523512/},

doi = {10.1016/j.phrs.2025.107826},

issn = {1096-1186},

year  = {2025},

date = {2025-08-01},

urldate = {2025-08-01},

journal = {Pharmacol Res},

volume = {218},

pages = {107826},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}