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Molecular Neurobiology

, Volume 56, Issue 4, pp 2728–2740 | Cite as

Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency

  • Michael F. SalvatoreEmail author
  • Tamara R. McInnis
  • Mark A. Cantu
  • Deana M. Apple
  • Brandon S. Pruett
Article
  • 329 Downloads

Abstract

Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson’s disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~ 40%) to nigral TH loss at bradykinesia onset in Parkinson’s disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging-related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~ 40%) 45–150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 h following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.

Keywords

Aging Parkinson’s Substantia nigra Tyrosine hydroxylase Movement Locomotor 

Notes

Acknowledgments

The authors acknowledge the outstanding animal care services provided by staff as well as resources provided by the Institute for Healthy Aging of the University of North Texas Health Science Center. We also thank Dr. Vicki A. Nejtek for her critical editorial comments on the manuscript.

Author Contribution

MFS conceived the work, analyzed the data, wrote the manuscript, and received funding to conduct the work. TRM, MAC, and BSP conducted the studies. TRM and MAC processed and analyzed the data. DMA provided critical comments and editing.

Funding Information

The work was funded by a grant award, AG040261, to MFS by the National Institute on Aging.

Compliance with Ethical Standards

Conflict of Interests

The authors declare that there are no competing interests.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute for Healthy Aging and Center for Neuroscience DiscoveryUniversity of North Texas Health Science CenterFort WorthUSA
  2. 2.Department of Cell Systems and Anatomy, Barshop Institute for Aging and Longevity StudiesUT Health San AntonioSan AntonioUSA
  3. 3.Department of Psychiatry and Human BehaviorWarren Alpert Medical School of Brown UniversityProvidenceUSA
  4. 4.Department of Pharmacology, Toxicology, & NeuroscienceLouisiana State University Health Sciences CenterShreveportUSA

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