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

Journal article

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.

Authors: Delgado-Goñi, T; Connor-Robson, N; Cioroch, M; Paisey, S; Marshall, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 15
• Issue: 1
• Pages: 15943-15943
• Article number: 15943
• Publication date: 2025-05-07
• Acceptance date: 2025-04-21
• DOI: 10.1038/s41598-025-99580-x
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: PET; Rat; [18F]fallypride; Parkinson’s disease; [18F]FDOPA; LRRK2