title: MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice.
abstract: In Parkinson's disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brain's capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated.
authors.affiliation: Dep. of Neurology, Charité University Medicine, CCM, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Lesemann
authors.forename: Claudia
authors.initials: C
authors.lastname: Reinel
authors.forename: Petra
authors.initials: P
authors.lastname: Hühnchen
authors.forename: Maximilian
authors.initials: M
authors.lastname: Pilhatsch
authors.forename: Rainer
authors.initials: R
authors.lastname: Hellweg
authors.forename: Philipp
authors.initials: P
authors.lastname: Klaissle
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
authors.forename: Barbara
authors.initials: B
authors.lastname: Steiner
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D003216:Conditioning, Operant / Q000187:drug effects; D003623:Dark Adaptation / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects*; D007381:Intermediate Filament Proteins / Q000235:genetics; D020267:MPTP Poisoning / Q000150:complications / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1 / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D001973:Bromodeoxyuridine; D004298:Dopamine; D005473:Fluoxetine; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D007381:Intermediate Filament Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D064231:Nestin; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C577485:Nes protein, mouse