Desipramine Modulation of α-, γ-Synuclein, and the Norepinephrine Transporter in an Animal Model of Depression
| Autor: | John G. McCarthy, Alexis M. Jeannotte, Eva E. Redei, Anita Sidhu |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty animal diseases Antidepressive Agents Tricyclic Microtubules Rats Inbred WKY chemistry.chemical_compound beta-Synuclein gamma-Synuclein Internal medicine Desipramine medicine Synuclein Family Animals Rats Wistar Neurotransmitter Cytoskeleton Pharmacology Depressive Disorder Norepinephrine Plasma Membrane Transport Proteins Behavior Animal biology Chemistry Nocodazole Frontal Lobe Rats nervous system diseases Disease Models Animal Psychiatry and Mental health Endocrinology nervous system Norepinephrine transporter Trillium alpha-Synuclein biology.protein Catecholamine Antidepressant Reuptake inhibitor Synaptosomes Behavioural despair test medicine.drug |
| Zdroj: | Neuropsychopharmacology. 34:987-998 |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/npp.2008.146 |
| Popis: | The mechanisms underlying depression remain elusive. We previously determined that alpha-synuclein (alpha-Syn) modulates the activity and trafficking of the norepinephrine transporter (NET) in a manner that is dependent on its interactions with microtubules (MTs). Here we sought to determine if alpha-Syn, or the other synuclein family members, beta-synuclein (beta-Syn) and gamma-synuclein (gamma-Syn), modulate NET activity in an animal model of depression, the Wistar-Kyoto (WKY) rat. The NET-selective antidepressant desipramine (DMI) was chronically administered for 14 days to WKY rats and the strain from which it was outbred that does not show depressive-like behavior, the Wistar rat. This drug regimen induced significant behavioral improvements in the WKY, but not the Wistar rat, in the forced swim test. In WKY rats there was an overexpression of gamma-Syn which was reduced following DMI treatment. In parallel, DMI caused an increase in both alpha-Syn and NET in the frontal cortex. Frontal cortex synaptosomes from WKY rats were not sensitive to nocodazole, a compound that promotes MT destabilization. However, in WKYs treated with DMI, nocodazole induced an increase in [(3)H]-NE uptake. This trend was reversed in Wistars. Underlying these DMI-induced changes were alterations in the protein interactions between the synucleins and NET with the tubulins. These results are the first to implicate alpha-Syn or gamma-Syn in the pathophysiology of depression and suggest that targeting synucleins may provide a new therapeutic option for depression. |
| Databáze: | OpenAIRE |
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