title: Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation.
abstract: Movement disorders are a common neurological complication of immunodeficiency virus infection and are thought to result from dopaminergic dysfunction in the basal ganglia. We measured levels of dopamine, and its metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid, in the putamen of healthy and simian immunodeficiency virus (SIV)-infected rhesus monkeys from infection until the development of AIDS. Changes in expression levels of cAMP response element binding protein (CREB), a transcription factor involved in the signalling pathway of dopamine, were also examined. Furthermore, we isolated microglia from the same animals and investigated their activation status in order to explore whether neurochemical findings are associated with immune activation. Plasma and CSF viral RNA load, T-cell analysis and basal ganglia histopathology provided information about disease progression in the animals. Putamen dopamine content was significantly reduced within 3 months of SIV infection, due to decreased dopamine synthesis initially, followed by loss of tyrosine hydroxylase-positive cells in substantia nigra, and accompanied by a decrease in total CREB expression. Pharmacological manipulation of dopaminergic tone with L-DOPA and selegiline showed that the reduction in CREB expression was due to reduced levels of dopamine. These neurochemical changes were significantly correlated with microglia activation in the absence of gross histopathological lesions. Our data demonstrate that putamen dopaminergic function is impaired during SIV infection and indicate that microglia may trigger endogenous mechanisms involved in the dysfunction of dopaminergic systems.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Scheller
authors.forename: Sieghart
authors.initials: S
authors.lastname: Sopper
authors.forename: Meta
authors.initials: M
authors.lastname: Jenuwein
authors.forename: Eva
authors.initials: E
authors.lastname: Neuen-Jacob
authors.forename: Thomas
authors.initials: T
authors.lastname: Tatschner
authors.forename: Edna
authors.initials: E
authors.lastname: Grünblatt
authors.forename: Volker
authors.initials: V
authors.lastname: ter Meulen
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.forename: Eleni
authors.initials: E
authors.lastname: Koutsilieri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000503:physiopathology* / Q000821:virology; D002469:Cell Separation; D002851:Chromatography, High Pressure Liquid; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D017628:Microglia / Q000502:physiology*; D011699:Putamen / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000503:physiopathology* / Q000821:virology; D009435:Synaptic Transmission / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D019562:Viral Load
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid