Challenges and Opportunities in Exploring Non-Motor Symptoms in 6-Hydroxydopamine Models of Parkinson's Disease: A Systematic Review

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non-motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6-hydroxydopamine (6-OHDA) rodent model is a well-established tool for preclinical research, replicating key motor and non-motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6-OHDA rodent models of PD to investigate non-motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6-OHDA PD models for experimental research of non-motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6-OHDA-based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co-occurrence of non-motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6-OHDA models in PD non-motor symptom research.