Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2 -R1441C rat model of early Parkinson’s disease revealed by in vivo PET imaging

Delgado-Goñi, Teresa, Connor-Robson, Natalie, Cioroch, Milena, Paisey, Stephen, Marshall, Christopher, Lane, Emma L. ORCID: https://orcid.org/0000-0001-8800-3764, Hauton, David, McCullagh, James, Magill, Peter J., Cragg, Stephanie J., Mackay, Clare E., Wade-Martins, Richard and Klein, Johannes C. 2025. Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2 -R1441C rat model of early Parkinson’s disease revealed by in vivo PET imaging. Scientific Reports 15 (1) , 15943. 10.1038/s41598-025-99580-x

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Abstract

We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits. LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	14 May 2025
Date of Acceptance:	21 April 2025
Last Modified:	14 May 2025 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178268

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