Abstract
The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central nervous system in response to sympathetic nervous system activation. In cultured hippocampal neurons, we have previously shown that norepinephrine induces increased expression of brain-derived neurotrophic factor (BDNF), the PI-3 K/Akt, MAPK pro-survival pathways, the BDNF receptor, TrkB, a transcription factor, and cyclic AMP response element binding protein (CREB). In the present study, we extend these findings of increased BDNF expression to its kinetics of release into the surrounding media. We also evaluate these two cell survival pathways, TrkB and CREB, in response to application of serotonin and/or norepinephrine. Serotonin elicits an earlier, but brief expression and release of BDNF, whereas norepinephrine elicits a more delayed and sustained release of BDNF. In response to both norepinephrine and 5-HT, the presence of BDNF in lysates and subsequent release into the media is significantly increased out to 4 h, as is PI-3 K/Akt activation. Together, these two neurotransmitters increase BDNF expression and release covering the entire 8 h continuum evaluated. The results of this study provide further evidence for a G protein-coupled receptor and a crosstalk-to-TrkB receptor with transactivation signaling across pathways.
Highlights
We have previously shown that hippocampal neurons in culture respond to application of norepinephrine by increasing expression of brain-derived neurotrophic factor (BDNF), its receptor, TrkB, activation of the PI-3 K and MAPK pathways, and the transcription factor, cyclic AMP response element binding protein (CREB) [24]
We demonstrated that in a dose- and time-response experiment, 10−7 M norepinephrine for 2 hr was maximally effective in eliciting BDNF expression; consistently, activation of TrkB was sustained for 4 hr and that of PI-3 K and MAPK pathways was maintained out to 8 hr [24,34]
We extend characterization of norepinephrine-induced expression of BDNF, within hippocampal neurons themselves, and, to the kinetics of BDNF release into the surrounding media (Figure 5(a))
Summary
Neuronal activity that increases as a result of sympathetic nervous system stimulation [1], such as physical activity [2,3,4] or administration of antidepressant drugs [5], has been shown to increase levels of peripheral [6] or CNS [4, 7,8,9] brain-derived neurotrophic factor (BDNF), and whether that activity is electrical stimulation [1,10], extracellular application of K+ [1,11,12,13,14,15,16,17] or Ca2+ [13] or application of excitatory neurotransmitter (e.g., kainic acid, [11,15, 18,19,20,21]), forskolin (cAMP activator [15]) or inhibitory neurotransmitter antagonist (CGP 52432, GABAB recaptor antagonist [15]). Anything that blocks neurotransmission, such as tetrodotoxin (Na+ channel blocker [10,12,22]), nifedipine [11,22], BAPTA-AM (intracellular Ca2+ chelator [12]) pertussis toxin (G-protein inhibitor [23]), Y 25130 (5-HT3 antagonist [15]) or AMPA or NMDA receptor blocker [21], has been shown to de-
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