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Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency

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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.

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References

  1. Carli M, Evenden JL, Robbins TW (1985) Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313:679–682

    Article  CAS  Google Scholar 

  2. Schultz W, Ruffieux A, Aebischer P (1983) The activity of pars compacta neurons of the monkey substantia nigra in relation to motor activation. Exp Brain Res 51:377–387

    Article  Google Scholar 

  3. Dodson PD et al (2016) Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism. Proc Natl Acad Sci 113:2180–2188

    Article  Google Scholar 

  4. Bergquist F, Shahabi HN, Nissbrandt H (2003) Somatodendritic dopamine release in rat substantia nigra influences motor performance on the accelerating rod. Brain Res 973:81–91

    Article  CAS  Google Scholar 

  5. da Silva JA, Tecuapetla F, Paixão V, Costa RM (2018) Dopamine neuron activity before action initiation gates and invigorates future movements. Nature 554:244–248

    Article  Google Scholar 

  6. Rech RH, Borys HK, Moore KE (1966) Alterations in behavior and brain catecholamine levels in rats treated with alpha-methyltyrosine. J Pharmacol Exp Ther 153:412–419

    CAS  PubMed  Google Scholar 

  7. Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman RM, Caron MG (1998) Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci 95:4029–4034

    Article  CAS  Google Scholar 

  8. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    Article  CAS  Google Scholar 

  9. Gasser T, Wichmann T, DeLong MR (2014) Neurobiology of brain disorders. Zigmond MJ et al. (eds) Ch. 19. Academic Press

  10. Fahn S (2010) Movement disorders: overview. In Encyclopedia of movement disorders, pp. 209–219. Kompoliti K, Metman LV (eds) Elsevier

    Chapter  Google Scholar 

  11. Bennet DA et al (1996) Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 334:71–76

    Article  Google Scholar 

  12. Murray AM et al (2004) A longitudinal study of parkinsonism and disability in a community population of older people. J Gerontol A Biol Sci Med Sci 59A:864–870

    Article  Google Scholar 

  13. Buchman AS, Wilson RS, Boyle PA, Bienias JL, Bennet DA (2007) Change in motor function and risk of mortality in older persons. J Am Geriatr Soc 55:11–19

    Article  Google Scholar 

  14. Buchman AS et al (2012) Nigral pathology and parkinsonian signs in elders without Parkinson disease. Ann Neurol 71:258–266

    Article  Google Scholar 

  15. Buchman AS et al (2016) Incident parkinsonism in older adults without Parkinson disease. Neurology 87:1036–1044

    Article  Google Scholar 

  16. Bezard E et al (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21:6853–6861

    Article  CAS  Google Scholar 

  17. Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301

    Article  Google Scholar 

  18. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455

    Article  CAS  Google Scholar 

  19. Marsden CD (1990) Parkinson’s disease. Lancet 335:948–952

    Article  CAS  Google Scholar 

  20. Marshall JF, Rosenstein AJ (1990) Age-related decline in rat striatal dopamine metabolism is regionally homogeneous. Neurobiol Aging 11:131–137

    Article  CAS  Google Scholar 

  21. Wolf ME et al (1991) Effect of aging on tyrosine hydroxylase protein content and the relative number of dopamine nerve terminals in human caudate. J Neurochem 56:1191–1200

    Article  CAS  Google Scholar 

  22. Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O (1992) Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem 58:642–648

    Article  CAS  Google Scholar 

  23. Emerich DF et al (1993) Locomotion of aged rats: relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons. Brain Res Bull 32:477–486

    Article  CAS  Google Scholar 

  24. Irwin I et al (1994) Aging and the nigrostriatal dopamine system: a non-human primate study. Neurodegeneration 3:251–265

    CAS  PubMed  Google Scholar 

  25. Emborg ME et al (1998) Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol 401:253–265

    Article  CAS  Google Scholar 

  26. Yurek M, Hipkens SB, Hebert MA, Gash DM, Gerhardt GA (1998) Age-related decline in striatal dopamine release and motoric function in Brown Norway/Fischer 344 hybrid rats. Brain Res 791:246–256

    Article  CAS  Google Scholar 

  27. Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM (2002) Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J Neurochem 80:168–177

    Article  CAS  Google Scholar 

  28. Haycock JW et al (2003) Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J Neurochem 87:574–585

    Article  CAS  Google Scholar 

  29. Collier TJ et al (2007) Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol Dis 26:56–65

    Article  CAS  Google Scholar 

  30. Cruz-Muros I et al (2007) Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments. Exp Neurol 204:147–161

    Article  CAS  Google Scholar 

  31. Salvatore MF, Pruett BS, Spann SL, Dempsey C (2009) Aging reveals a role for nigral tyrosine hydroxylase ser31 phosphorylation in locomotor activity generation. PLoS ONE e08466

  32. Orosz D, Bennett JP (1992) Simultaneous micordialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the hemiparkinsonian rat. Exp Neurol 115:388–393

    Article  CAS  Google Scholar 

  33. Hoffer BJ et al (1994) Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci Lett 182:107–111

    Article  CAS  Google Scholar 

  34. Gash DM et al (1996) Functional recovery in Parkinsonian monkeys treated with GDNF. Nature 380:252–255

    Article  CAS  Google Scholar 

  35. Collier TJ et al (2002) Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson’s disease. J Comp Neurol 42:320–330

    Article  Google Scholar 

  36. Goldberg MS et al (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1. Neuron 45:489–496

    Article  CAS  Google Scholar 

  37. Andersson DR, Nissbrandt H, Bergquist F (2006) Partial depletion of dopamine in substantia nigra impairs motor performance without altering striatal dopamine neurotransmission. Eur J Neurosci 24:617–624

    Article  Google Scholar 

  38. Allen E, Carlson KM, Zigmond MJ, Cavanaugh JE (2011) L-DOPA reverses motor deficits associated with normal aging in mice. Neurosci Lett 489:1–4

    Article  CAS  Google Scholar 

  39. Pruett BS, Salvatore MF (2013) Nigral GFR-α1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity. Mol Neurobiol 47:989–999

    Article  Google Scholar 

  40. Salvatore MF et al (2016) Initiation of calorie restriction in middle-aged male rats attenuates aging-related motoric decline and bradykinesia without increased striatal dopamine. Neurobiol Aging 37:192–207

    Article  CAS  Google Scholar 

  41. Kordower JH et al (2017) Robust graft survival and normalized dopaminergic innervation does not obligate recovery in a PD patient. Ann Neurol 81:46–57

    Article  CAS  Google Scholar 

  42. Robertson GS, Robertson HA (1989) Evidence that L-DOPA-induced rotational behavior is dependent on both striatal and nigral mechanisms. J Neurosci 9:3326–3331

    Article  CAS  Google Scholar 

  43. Gerhardt GA, Cass WA, Huettl P, Brock S, Zhang Z, Gash DM (1999) GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys. Brain Res 817:163–171

    Article  CAS  Google Scholar 

  44. O'Dell SJ, Gross NB, Fricks AN, Casiano BD, Nguyen TB, Marshall JF (2007) Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection. Neuroscience 144:1141–1151

    Article  CAS  Google Scholar 

  45. Kirik D, Rosenblad C, Bjorklund A, Mandel RJ (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci 20:4686–4700

    Article  CAS  Google Scholar 

  46. Goldberg NR, Fields V, Pflibsen L, Salvatore MF, Meshul CK (2012) Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Neurobiol Dis 45:1051–1067

    Article  Google Scholar 

  47. Smith BA, Goldberg NR, Meshul CK (2011) Effects of treadmill exercise on behavioral recovery and neural changes in the substantia nigra and striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse. Brain Res 1386:70–80

    Article  CAS  Google Scholar 

  48. Salvatore MF et al (2017) Dissociation of striatal dopamine and tyrosine hydroxylase expression from aging-related motor decline: evidence from calorie restriction intervention. J Gerontol A Biol Sci Med Sci 73:11–20

    Article  Google Scholar 

  49. Buchman AS, Dawe RJ, Yu L, Lim A, Wilson RS, Schneider JA, Bennett DA (2018) Brain pathology is related to total daily physical activity in older adults. Neurology 10:1212

    Google Scholar 

  50. Geffen LB, Jessell TM, Cuello AC, Iversen LL (1976) Release of dopamine from dendrites in rat substantia nigra. Nature 260:258–260

    Article  CAS  Google Scholar 

  51. Rice ME, Patel JC (2015) Somatodendritic dopamine release: recent mechanistic insights. Philos Trans R Soc Lond Ser B Biol Sci 370:20140185. https://doi.org/10.1098/rstb.2014.0185

    Article  CAS  Google Scholar 

  52. Windels F, Kiyatkin EA (2006) Dopamine action in the substantia nigra pars reticulata: iontophoretic studies in awake, unrestrained rats. Eur J Neurosci 24:1385–1394

    Article  Google Scholar 

  53. Kliem MA, Maidment NT, Ackerson LC, Chen S, Smith Y, Wichmann T (2007) Activation of nigral and pallidal dopamine D1-like receptors modulates basal ganglia outflow in monkeys. J Neurophysiol 98:489–1500

    Article  Google Scholar 

  54. Trevitt JT, Carlson BB, Nowend K, Salamone JD (2004) Substantia nigra pars reticulate is a highly potent site of action for the behavioral effects of the D1 antagonist SCH23390 in rat. Psychopharmacol 156:32–41

    Google Scholar 

  55. Andersson DR, Bjornsson E, Bergquist F, Nissbrandt H (2009) Motor activity-induced dopamine release in the substantia nigra is regulated by muscarinic receptors. Exp Neurol 221:251–259

    Article  Google Scholar 

  56. Sanchez HL et al (2008) Dopaminergic mesencephalic systems and behavioral performance in very old rats. Neuroscience 154:1598–1606

    Article  CAS  Google Scholar 

  57. Ross GW et al (2004) Parkinsonian signs and substantia nigra neuron density in descendents elders without PD. Ann Neurol 56:532–539

    Article  Google Scholar 

  58. Rudow G et al (2008) Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 115:461–470

    Article  Google Scholar 

  59. Salvatore MF, Pruett BS (2012) Dichotomy of tyrosine hydroxylase and dopamine regulation between somatodendritic and terminal field areas of nigrostriatal and mesoaccumbens pathways. PLoS One 7:e29867

    Article  CAS  Google Scholar 

  60. Salvatore MF (2014) ser31 tyrosine hydroxylase phosphorylation parallels differences in dopamine recovery in nigrostriatal pathway following 6-OHDA lesion. J Neurochem 129:548–558

    Article  CAS  Google Scholar 

  61. Salvatore MF, Calipari E, Jones SR (2016) Regulation of tyrosine hydroxylase expression and phosphorylation in dopamine transporter-deficient mice. ACS Chem Neurosci 7:941–951

    Article  CAS  Google Scholar 

  62. Yin D, Forsayeth J, Bankiewicz KS (2010) Optimized cannula design and placement for convection-enhanced delivery in rat striatum. J Neurosci Methods 187:46–51

    Article  Google Scholar 

  63. Watanabe et al (2005) Effects of alpha-methyl-pi-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats. J Oral Sci 47:185–190

    Article  CAS  Google Scholar 

  64. Parker EM, Cubeddu LX (1986) Effects of d-amphetamine and dopamine synthesis inhibitors on dopamine and acetylcholine neurotransmission in the striatum. I. Release in the absence of vesicular transmitter stores. J Pharmacol Exp Ther 237:179–192

    CAS  PubMed  Google Scholar 

  65. Suaud-Chagny MF, Buda M, Gonon FG (1989) Pharmacology of electrically evoked dopamine release studied in the rat olfactory tubercle by in vivo electrochemistry. Eur J Pharmacol 164:273–283

    Article  CAS  Google Scholar 

  66. Arnold JC et al (2017) Aging-related limit of exercise efficacy on motor decline. PLoS One 12:e0188538

    Article  Google Scholar 

  67. Sorond FA et al (2015) Aging, the central nervous system, and mobility in older adults: neural mechanisms of mobility impairment. J Gerontol A Biol Sci Med Sci 70:1526–1532

    Article  Google Scholar 

  68. Fleischman DA, Wilson RS, Schneider JA, Beinias JL, Bennet DA (2007) Parkinsonian signs and functional disability in old age. Exp Aging Res 33:59–76

    Article  Google Scholar 

  69. Buchman AS, Wilson RS, Shulman JM, Leurgans SE, Schneider JA, Bennett DA (2016) Parkinsonism in older adults and its association with adverse health outcomes and neuropathology. J Gerontol A Biol Sci Med Sci 71:549–556

    Article  Google Scholar 

  70. Pijnenburg AJJ, Honig WMM, Van Der Heyden JAM, Van Rossum JM (1976) Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity. Eur J Pharmacol 35:45–58

    Article  CAS  Google Scholar 

  71. Kas MJH, van den Bos R, Baars AM, Lubbers M, Lesscher HMB, Hillebrand JJG, Schuller AG, Pintar JE et al (2004) Mu-opioid receptor knockout mice show diminished food-anticipatory activity. Eur J Neurosci 20:1624–1632

    Article  Google Scholar 

  72. Ingram DK (2000) Age-related decline in physical activity: generalization to nonhumans. Med Sci Sports Exerc 32:1623–1629

    Article  CAS  Google Scholar 

  73. Arnold JC, Salvatore MF (2016) Exercise-mediated increase in nigral tyrosine hydroxylase is accompanied by increased nigral GFR-α1 and EAAC1 expression in aging rats. ACS Chem Neurosci 7:227–239

    Article  CAS  Google Scholar 

  74. Glajch KE, Fleming SM, Surmeier DJ, Osten P (2012) Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson’s disease. Behav Brain Res 230:309–316

    Article  CAS  Google Scholar 

  75. Dirr ER, Ekhator OR, Blackwood R, Holden JG, Masliah E, Schultheis PJ, Fleming SM (2018) Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein. Behav Brain Res 343:41–49

    Article  CAS  Google Scholar 

  76. Kanaan NM, Kordower JH, Collier TJ (2008) Age-related changes in dopamine trnasporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons. Relevance in selective neuronal vulnerability to degeneration. Eur J Neurosci 27:3205–3215

    Article  CAS  Google Scholar 

  77. Amalric M, Koob GF (1987) Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats. J Neurosci 7:2129–2134

    Article  CAS  Google Scholar 

  78. Smith AD, Amalric M, Koob GF, Zigmond MJ (2002) Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time. Neuropsychopharmacology 26:756–764

    Article  CAS  Google Scholar 

  79. Mourre C et al (2017) Changes in SK channel expression in the basal ganglia after partial Nigrostriatal dopamine lesions in rats: functional consequences. Neuropharmacology 113:519–532

    Article  CAS  Google Scholar 

  80. Ztaou S et al (2016) Involvement of striatal cholinergic interneurons and M1 and M4 muscarinic receptors in motor symptoms of Parkinson’s disease. J Neurosci 36:9161–9172

    Article  CAS  Google Scholar 

  81. Moehle MS et al (2017) Cholinergic projections to the substantia nigra pars reticulate inhibit dopamine modulation of basal ganglia through the M4 muscarinic receptor. Neuron 96:1358–1372

    Article  CAS  Google Scholar 

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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.

Funding

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

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Authors and Affiliations

  1. Institute for Healthy Aging and Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA

    Michael F. Salvatore, Tamara R. McInnis & Mark A. Cantu

  2. Department of Cell Systems and Anatomy, Barshop Institute for Aging and Longevity Studies, UT Health San Antonio, San Antonio, TX, 78229, USA

    Deana M. Apple

  3. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, 02912, USA

    Brandon S. Pruett

  4. Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA

    Brandon S. Pruett

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  1. Michael F. Salvatore
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  2. Tamara R. McInnis
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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.

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Correspondence to Michael F. Salvatore.

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Salvatore, M.F., McInnis, T.R., Cantu, M.A. et al. Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency. Mol Neurobiol 56, 2728–2740 (2019). https://doi.org/10.1007/s12035-018-1256-9

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