title: Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism.
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.
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Paumier
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Madhavan
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Terpstra
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Celano
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Green
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Nastassja M
authors.initials: NM
authors.lastname: Imus
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Marckini
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Daley
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Steece-Collier
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Collier
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000639:Amitriptyline / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D005518:Food Preferences; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension; D008297:Male; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012439:Saccharin / Q000008:administration & dosage; D013378:Substantia Nigra / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D018712:Analgesics, Non-Narcotic; D019208:Brain-Derived Neurotrophic Factor; D000639:Amitriptyline; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D012439:Saccharin