title: Differential BDNF responses of triple versus dual reuptake inhibition in neuronal and astrocytoma cells as well as in rat hippocampus and prefrontal cortex.
abstract: Monoamine reuptake inhibitors increase brain-derived neurotrophic factor (BDNF) activity, and this growth factor is regarded as an interesting target for developing new antidepressant drugs. The aims of this study were to evaluate whether monoaminergic reuptake inhibition increases BDNF in vivo and in vitro as predicted by the neurotrophic hypothesis of depression, and whether triple reuptake inhibition has a superior BDNF response compared to dual reuptake inhibition. Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. The prefrontal cortex contained increased BDNF levels only after DOV 216,303 treatment. In vitro, neither duloxetine nor DOV 216,303 altered intracellular BDNF levels in murine HT22 neuronal cells. In contrast, BDNF release was more effectively decreased following treatment with DOV 216,303 in these cells. In rat C62B astrocytomas, both antidepressants increased intracellular BDNF levels at their highest nontoxic concentration. C62B astrocytomas did not release BDNF, even after antidepressant treatment. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell-cell interactions, and different mechanisms of action of antidepressants used.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. jos.prickaerts@maastrichtuniversity.nl
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: Jochen
authors.initials: J
authors.lastname: De Vry
authors.forename: Janneke
authors.initials: J
authors.lastname: Boere
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.forename: Maria S
authors.initials: MS
authors.lastname: Quinton
authors.forename: Sharon
authors.initials: S
authors.lastname: Engel
authors.forename: Larry
authors.initials: L
authors.lastname: Melnick
authors.forename: Rudy
authors.initials: R
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001254:Astrocytoma; D001372:Aza Compounds / Q000494:pharmacology*; D001932:Brain Neoplasms; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D000068736:Duloxetine Hydrochloride; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; D000928:Antidepressive Agents; D001372:Aza Compounds; D019208:Brain-Derived Neurotrophic Factor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014179:Neurotransmitter Uptake Inhibitors; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride