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In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease

Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent...

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Autores principales: Callahan, Joshua W., Abercrombie, Elizabeth D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139944/
https://www.ncbi.nlm.nih.gov/pubmed/21811446
http://dx.doi.org/10.3389/fnsys.2011.00061
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author Callahan, Joshua W.
Abercrombie, Elizabeth D.
author_facet Callahan, Joshua W.
Abercrombie, Elizabeth D.
author_sort Callahan, Joshua W.
collection PubMed
description Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent in HD we examined DA neurotransmission in the striatum in transgenic (tg) murine models of HD. We used in vivo microdialysis to compare extracellular concentrations of striatal DA in both a fragment (R6/2) model, which displays a rapid and severe phenotype, and a full-length (YAC128) model that expresses a more progressive phenotype. Extracellular striatal DA concentrations were significantly reduced in R6/2 mice and decreased concomitantly with age-dependent increasing motor impairments on the rotarod task (7, 9, and 11 weeks). In a sample of 11-week-old R6/2 mice, we also measured tissue concentrations of striatal DA and found that total levels of DA were significantly depleted. However, the loss of total DA content (<50%) was insufficient to account for the full extent of DA depletion in the extracellular fluid (ECF; ∼75%). We also observed a significant reduction in extracellular DA concentrations in the striatum of 7-month-old YAC128 mice. In a separate set of experiments, we applied d-amphetamine (AMPH; 10 μm) locally into the striatum to stimulate the release of intracellular DA into the ECF. The AMPH-induced increase in extracellular DA levels was significantly blunted in 9-week-old R6/2 mice. There also was a decrease in AMPH-stimulated DA efflux in 7-month-old YAC128 mice in comparison to WT controls, although the effect was milder. In the same cohort of 7-month-old YAC128 mice we observed a significant reduction in the total locomotor activity in response to systemic AMPH (2 mg/kg). Our data demonstrate that extracellular DA release is attenuated in both a fragment and full-length tg mouse model of HD and support the concept of DA involvement in aspects of the syndrome.
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spelling pubmed-31399442011-08-02 In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease Callahan, Joshua W. Abercrombie, Elizabeth D. Front Syst Neurosci Neuroscience Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent in HD we examined DA neurotransmission in the striatum in transgenic (tg) murine models of HD. We used in vivo microdialysis to compare extracellular concentrations of striatal DA in both a fragment (R6/2) model, which displays a rapid and severe phenotype, and a full-length (YAC128) model that expresses a more progressive phenotype. Extracellular striatal DA concentrations were significantly reduced in R6/2 mice and decreased concomitantly with age-dependent increasing motor impairments on the rotarod task (7, 9, and 11 weeks). In a sample of 11-week-old R6/2 mice, we also measured tissue concentrations of striatal DA and found that total levels of DA were significantly depleted. However, the loss of total DA content (<50%) was insufficient to account for the full extent of DA depletion in the extracellular fluid (ECF; ∼75%). We also observed a significant reduction in extracellular DA concentrations in the striatum of 7-month-old YAC128 mice. In a separate set of experiments, we applied d-amphetamine (AMPH; 10 μm) locally into the striatum to stimulate the release of intracellular DA into the ECF. The AMPH-induced increase in extracellular DA levels was significantly blunted in 9-week-old R6/2 mice. There also was a decrease in AMPH-stimulated DA efflux in 7-month-old YAC128 mice in comparison to WT controls, although the effect was milder. In the same cohort of 7-month-old YAC128 mice we observed a significant reduction in the total locomotor activity in response to systemic AMPH (2 mg/kg). Our data demonstrate that extracellular DA release is attenuated in both a fragment and full-length tg mouse model of HD and support the concept of DA involvement in aspects of the syndrome. Frontiers Research Foundation 2011-07-15 /pmc/articles/PMC3139944/ /pubmed/21811446 http://dx.doi.org/10.3389/fnsys.2011.00061 Text en Copyright © 2011 Callahan and Abercrombie. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
spellingShingle Neuroscience
Callahan, Joshua W.
Abercrombie, Elizabeth D.
In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title_full In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title_fullStr In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title_full_unstemmed In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title_short In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full-Length (YAC128) Transgenic Mouse Models of Huntington's Disease
title_sort in vivo dopamine efflux is decreased in striatum of both fragment (r6/2) and full-length (yac128) transgenic mouse models of huntington's disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139944/
https://www.ncbi.nlm.nih.gov/pubmed/21811446
http://dx.doi.org/10.3389/fnsys.2011.00061
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