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venlafaxine snri brain

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#1 Ruth

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Posted 29 October 2018 - 04:48 AM

https://i.imgur.com/29oJ1Fs.png "To evaluate VLX’s effects at a therapeutically relevant time point we analyzed transcriptomic changes in the FC of DA rats after 3 weeks-long VLX treatment (40 mg/kg/die via osmotic minipumps). Chronic VLX administration had positive effects on neurotransmitter release and upregulated neuroplasticity, axonogenesis and cognitive function related gene sets, besides significantly elevated expression of individual genes related to these processes. Interestingly, VLX was also able to alter the expression of genes involved in mitochondrial antioxidant activity and the insulin signaling pathways, suggesting so far unidentified mechanisms of action"

In the FC of DA rats following chronic VLX treatment in a therapeutic dose “regulation of synaptic plasticity (NES=1.79)”, “synapse organization (NES=1.59)”, “neuron-neuron synaptic transmission (NES=1.71)” or “neuron projection terminus (NES=1.67)” were upregulated. We found increases in the expression of Trk genes (Ntrk2, Ntrk3). These tyrosine kinases are transmembrane receptors stimulated by neurotrophins (e.g. BDNF, NT-3 or NT-4). They promote neuron survival, while polymorphisms and decreased expression of these genes showed associations with mood disorders [189, 190]. Abnormalities in glutamatergic neurotransmission paralleled MDD [191] and chronic treatment with antidepressants have been shown to influence the glutamatergic system through the AMPA3 receptor in the hippocampus [192], which was also upregulated by our paradigm. Additional genes coding NMDA-receptors were also upregulated, namely
Grin2a and Grin2b, while a polymorphism in the latter was associated with MDD [193]. Besides such direct relations, glutamatergic signaling via these receptors is involved in synaptic plasticity and long-term potentiation [194, 195]. Glutamatergic cation channels, like NMDA-channels activate second messenger systems, related primarily to Ca-signaling. Our results show that Camk2b and Camk2g, calcium/calmodulin dependent kinases were upregulated following chronic VLX treatment. Since these transcripts showed elevated expression in MDMA treated animals, these alterations are probably unrelated to the changes in glutamatergic genes. Whatever the underlying cause, the fact that Camk2 activation accompanies antidepressant-like effects further support the importance of the elevated mRNA levels of these genes in the current experiment [196]. In addition to signaling via ion channels, Gnaq and Gnao showed elevated expression in the FC following chronic VLX treatment. Gnao represents the Gα0 unit of G-protein coupled receptors and its activation causes a decrease in intracellular cAMP levels; Gnaq codes the Gαq subunit coupling to 7-transmembrane receptors and is involved in second-messenger systems related to intracellular signaling via phospholipase Cβ [197]. Consequently, G-protein coupled receptors are probably involved in the wide scale changes following chronic VLX treatment. The Cd47 protein participates in the regulation of neuronal networks and Cd47-deficient mice showed prolonged immobility (depression like behavior) in the FST [198]. Mmp9, another gene also induced by VLX treatment, is involved in synaptic plasticity and cognitive processes. Mice over-expressing Mmp9 showed enhanced performance in the novel object recognition and the Morris water-maze tasks and these effects were paralleled by increased dendritic spine density in the hippocampus and the cortex [199]. Astroglial cells may also play a role in the effects of VLX. Gfap, the glial fibrillary acidic protein is involved in the regulation of the shape and function of astroglia [36]. Reductions of Gfap in astrocytes seemed to be involved in MDD [200]. In our study Gfap was downregulated underlining the need for further experiments delineating the exact role of Gfap and astroglia in the pathophysiology of MDD.

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