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Summary   Introduction  Mutations in leucine‐rich repeat kinase 2 ( LRRK 2) are the most prevalent cause of familial and sporadic Parkinson's disease ( PD ). Because most pathogenic  LRRK 2 mutations result in enhanced kinase activity, it suggests that  LRRK 2 inhibitors may serve as a potential treatment for  PD . To evaluate whether  LRRK 2 inhibitors are effective therapies for  PD , it is crucial to know whether  LRRK 2 inhibitors will affect dopaminergic ( DA ergic) neurotransmission. However, to date, there is no study to investigate the impact of  LRRK 2 inhibitors on  DA ergic neurotransmission.    Aims  To address this gap in knowledge, we examined the effects of three types of  LRRK 2 inhibitors ( LRRK 2‐ IN ‐1,  GSK 2578215A, and  GNE ‐7915) on dopamine ( DA ) release in the dorsal striatum using fast‐scan cyclic voltammetry and  DA  neuron firing in the substantia nigra pars compacta ( SN pc) using patch clamp in mouse brain slices.    Results  We found that  LRRK 2‐ IN ‐1 at a concentration higher than 1  μ M causes off‐target effects and decreases  DA  release, whereas  GSK 2578215A and  GNE ‐7915 do not. All three inhibitors at 1  μ M have no effect on  DA  release and  DA  neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical  LRRK 2 mouse models (i.e.,  BAC  transgenic  hG 2019S and  hR 1441G) and demonstrated that  GNE ‐7915 enhances  DA  release and synaptic vesicle mobilization/recycling.    Conclusion   GNE ‐7915 can be validated for further therapeutic development for  PD .

Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission