Abstract
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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Acknowledgements
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.
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Paumier, K., Sortwell, C., Madhavan, L. et al. Chronic Amitriptyline Treatment Attenuates Nigrostriatal Degeneration and Significantly Alters Trophic Support in a Rat Model of Parkinsonism. Neuropsychopharmacol 40, 874–883 (2015). https://doi.org/10.1038/npp.2014.262
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DOI: https://doi.org/10.1038/npp.2014.262
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