TY - JOUR
T1 - Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism
AU - Paumier, Katrina L.
AU - Sortwell, Caryl E.
AU - Madhavan, Lalitha
AU - Terpstra, Brian
AU - Celano, Stephanie L.
AU - Green, Joshua J.
AU - Imus, Nastassja M.
AU - Marckini, Nathan
AU - Daley, Brian
AU - Steece-Collier, Kathy
AU - Collier, Timothy J.
N1 - Funding Information:
This work was supported by the Davis Phinney Foundation for Parkinson’s, the Morris K. Udall Center of Excellence for Parkinson’s disease Research at Michigan State University, and the University of Cincinnati (NS 058830). We wish to acknowledge the intellectual contributions of Nick Kanaan, Katherine Soderstrom, and technical expertise of Brian Daley, Allison Cole-Strauss, Emeline Tolod-Kemp, and Nate Levine. Special thanks to Sara Gombash and Valerie Thompson for their late night support in the lab.
Funding Information:
Dr Paumier was supported by funding from the Davis Phinney Foundation for Parkinson’s disease. Drs Paumier, Madhavan, and Collier were supported by the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Michigan State University and the University of Cincinnati (NS 058830). Dr Collier also receives support from the Michael J. Fox Foundation and is compensated as an associate editor for the European Journal of Neuroscience. Dr Terpstra, Dr Steece-Collier, Ms Celano, Mr Green, Ms Imus, Mr Marckini, and Mr Daley have nothing to disclose. All funding sources provided unrestricted support and had no role in the oversight or review of the research data or reporting.
Publisher Copyright:
© 2015 American College of Neuropsychopharmacology. All rights reserved.
PY - 2015/3
Y1 - 2015/3
N2 - In addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival.
AB - In addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival.
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UR - http://www.scopus.com/inward/citedby.url?scp=84925533286&partnerID=8YFLogxK
U2 - 10.1038/npp.2014.262
DO - 10.1038/npp.2014.262
M3 - Article
C2 - 25267343
AN - SCOPUS:84925533286
SN - 0893-133X
VL - 40
SP - 874
EP - 883
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 4
ER -