Objective: Inhibition of tyrosine hydroxylase activity in the substantia nigra (SN) produces a significant reduction in locomotor motor activity commensurate with decreased dopamine (DA) content in the SN, without effect in striatum [1].  Here, we evaluated the impact of inhibition of dopamine uptake in SN and striatum on locomotor activity.

Background: Evidence from a number of clinical and preclinical studies in Parkinson’s disease (PD) and aging suggest a mismatch of DA levels in striatum against anticipated impact on motor activity, suggesting striatal DA is not a consistent metric to predict motor function.  Despite these results, a striato-centric viewpoint predominates in evaluation the role of DA in locomotor function.  Consideration of the impact of nigral DA upon motor function is remote.   Results from our lab and few others support the possibility that nigral DA may alone influence the parameter of movement initiation or continuation, the lack of which (akinesia/bradykinesia) is a cardinal symptom of PD.

Method: We took a two-step approach using aged (18 month old) male Brown-Norway Fischer 344 F1 hybrid (BNF) rats, which have been reported to have decreased locomotor activity at this time in their lifespan.  In the first study, we analyzed DA contemporaneously by in vivo microdialysis in dorsal striatum and ventral lateral SN, after infusion of nomifensine (NOM) in either the striatum or SN, evaluating changes in DA levels in each region prior to during and after NOM.  In the second study, 18 month old male BNF rats were implanted with guide cannula to target striatum or SN to locally infuse saline or NOM (each infusion on separate days) to analyze locomotor activity in the open-field for 3 hours in a within-subjects design.

Results: Infusion of NOM into the SN or striatum increased DA levels into the region infused with NOM, without significant effect on DA levels in the non-infused region.  Infusion of NOM into striatum did not affect movement number (MN) as compared to that following saline (NOM, F(1,3)=0.537, p=0.52), whereas NOM infusion into SN increased MN (NOM, F(1,7)=5.79, p=0.047).

Conclusion: These preliminary results indicate that DA signaling in the SN may be an important component of nigrostriatal function in movement initiation or continuation.

References: [1] Salvatore MF, et al. (2019) Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency. Mol Neurobiol 56: 2728-2740.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/compartment-specific-blockade-of-dopamine-uptake-in-nigrostriatal-pathway-reveals-role-for-nigral-dopamine-function-in-movement-frequency-in-open-field/