TY - JOUR
T1 - Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency
AU - Salvatore, Michael F.
AU - McInnis, Tamara R.
AU - Cantu, Mark A.
AU - Apple, Deana M.
AU - Pruett, Brandon S.
N1 - Funding Information:
Funding Information The work was funded by a grant award, AG040261, to MFS by the National Institute on Aging.
Funding Information:
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.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Aging
KW - Locomotor
KW - Movement
KW - Parkinson’s
KW - Substantia nigra
KW - Tyrosine hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=85050919560&partnerID=8YFLogxK
U2 - 10.1007/s12035-018-1256-9
DO - 10.1007/s12035-018-1256-9
M3 - Article
C2 - 30056575
AN - SCOPUS:85050919560
SN - 0893-7648
VL - 56
SP - 2728
EP - 2740
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 4
ER -