Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies
Article first published online: 16 JAN 2004
Copyright © 2004 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 75, Issue 4, pages 451–460, 15 February 2004
How to Cite
Khawaja, X., Xu, J., Liang, J.-J. and Barrett, J. E. (2004), Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies. J. Neurosci. Res., 75: 451–460. doi: 10.1002/jnr.10869
- Issue published online: 20 JAN 2004
- Article first published online: 16 JAN 2004
- Manuscript Accepted: 15 OCT 2003
- Manuscript Revised: 14 OCT 2003
- Manuscript Received: 14 AUG 2003
It is recognized that monoamine reuptake inhibitors (MARIs) exert beneficial effects in the treatment of major depression and general anxiety disorder. The aim of this study was to identify proteins regulated by this class of antidepressant using a proteome differential profiling approach. Either venlafaxine or fluoxetine was administered systemically to adult rats for 2 weeks, and protein patterns from rat hippocampal cytosolic extracts were compared by two-dimensional gel electrophoresis. Silver-stained protein spots displaying differential expression were identified by mass spectrometry. Thirty-three protein spots were modulated by both drug treatments compared to controls. The classification of several proteins that were sorted by function suggested convergent pathway activities for both MARIs at the post-receptor level. These included proteins associated with neurogenesis (insulin like growth factor 1 (IGF-1), glia maturation factor [GMF]-β), outgrowth/maintenance of neuronal processes (hippocampal cholinergic neurostimulating peptide [HCNP], PCTAIRE-3), and with neural regeneration/axonal guidance collapsin response mediator protein (CRMP-2) systems. Other modulated proteins indicated an increase in neuronal vesicular cell trafficking and synaptic plasticity (Ras-related protein 4a (Rab4a), Ras-related protein 1b (Rab1b), heat shock protein 10 [HSP10]), as well as neurosteroidogenic (hydroxysteroid sulfotransferase A) and possible anti-apoptotic (dimethylargininase-1 L-N,N-dimethylarginine dimethylaminohydrolase-1 [DDAH-1], pyruvate dehydrogenase-E1 [PDH-E1], antioxidant protein-2 [AOP-2]) pathway-mediated regulatory events. Parallel studies to investigate further the effects of venlafaxine and fluoxetine on adult hippocampal neurogenesis in vivo by quantitative bromodeoxyuridine immunolabeling revealed a significant drug-induced increase in the proliferation rate and long-term survivability of progenitor stem cells located in the subgranular zone. These data suggest that MARIs share wide-ranging proteome changes within the hippocampal formation, beyond 5-HT/NE neurotransmission. This may reflect long-term functional adaptations required for antidepressant activity. © 2004 Wiley-Liss, Inc.