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...
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Elsevier
2025-08-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825002518 |
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| author | Alexandra H. Evans Marc Ciruela-Jardí William Rea Bradley M. Keegan Marjorie R. Levinstein Alessandro Bonifazi Jianjing Cao Shelley N. Jackson Lei Shi Nil Casajuana-Martin Ning-Sheng Cai Vicent Casadó Christopher J. Earley Amy H. Newman Michael Michaelides Leonardo Pardo Estefanía Moreno Sergi Ferré |
| author_facet | Alexandra H. Evans Marc Ciruela-Jardí William Rea Bradley M. Keegan Marjorie R. Levinstein Alessandro Bonifazi Jianjing Cao Shelley N. Jackson Lei Shi Nil Casajuana-Martin Ning-Sheng Cai Vicent Casadó Christopher J. Earley Amy H. Newman Michael Michaelides Leonardo Pardo Estefanía Moreno Sergi Ferré |
| author_sort | Alexandra H. Evans |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7c442476baee47efb3cac2234a75ff8b |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-7c442476baee47efb3cac2234a75ff8b2025-08-20T02:45:42ZengElsevierPharmacological Research1096-11862025-08-0121810782610.1016/j.phrs.2025.107826Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromerAlexandra H. Evans0Marc Ciruela-Jardí1William Rea2Bradley M. Keegan3Marjorie R. Levinstein4Alessandro Bonifazi5Jianjing Cao6Shelley N. Jackson7Lei Shi8Nil Casajuana-Martin9Ning-Sheng Cai10Vicent Casadó11Christopher J. Earley12Amy H. Newman13Michael Michaelides14Leonardo Pardo15Estefanía Moreno16Sergi Ferré17Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USALaboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain; Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, SpainIntegrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USAComputational Chemistry and Molecular Biophysics Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USABiobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USAMedicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USAMedicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USATranslational Analytical Core, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USAComputational Chemistry and Molecular Biophysics Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USALaboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, SpainIntegrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USALaboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, SpainDepartment of Neurology and Sleep Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USAMedicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USABiobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USALaboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, SpainLaboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain; Corresponding authors.Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S1043661825002518Dopamine D1 receptorDopamine D3 receptorHeteromersStriatumβ-arrestinLocomotor activity |
| spellingShingle | Alexandra H. Evans Marc Ciruela-Jardí William Rea Bradley M. Keegan Marjorie R. Levinstein Alessandro Bonifazi Jianjing Cao Shelley N. Jackson Lei Shi Nil Casajuana-Martin Ning-Sheng Cai Vicent Casadó Christopher J. Earley Amy H. Newman Michael Michaelides Leonardo Pardo Estefanía Moreno Sergi Ferré Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer Pharmacological Research Dopamine D1 receptor Dopamine D3 receptor Heteromers Striatum β-arrestin Locomotor activity |
| title | Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer |
| title_full | Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer |
| title_fullStr | Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer |
| title_full_unstemmed | Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer |
| title_short | Locomotor activity depends on β-arrestin recruitment by the dopamine D1 receptor in the striatal D1-D3 receptor heteromer |
| title_sort | locomotor activity depends on β arrestin recruitment by the dopamine d1 receptor in the striatal d1 d3 receptor heteromer |
| topic | Dopamine D1 receptor Dopamine D3 receptor Heteromers Striatum β-arrestin Locomotor activity |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825002518 |
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