Andreetta, Filippo (2012)
Ph.D. thesis, University of Birmingham.
Serotonin (5-HT) is a neurotransmitter that is mainly expressed in brain where serves a wide array of physiological and behavioural functions. Literature described that some mediators of inflammation (i.e. cytokines) have been implicated in the modulation of monoaminergic response and this may be associated with pathophysiology of depression and in the responsiveness of antidepressant treatment in both humans and animals (Capuron and Miller, 2011). A hypothesis suggests that cytokines may affect the serotonergic system through p38 MAP kinase dependent mechanisms particularly at the serotonin transporters (Zhu et al., 2006) and 5HT7 receptors (Lieb et al., 2005; Mahe et al., 2005). The aim of this study was to show the interaction of Interleukin 1β (IL-1β) or p38 MAP kinase on serotonin transporter (SERT) and 5HT7 receptors in cells lines and native tissue, highlighting the biochemical mechanism of this system. The IL-1β and p38 MAP kinase activator, anisomycin, did not show any effect on 5-HT uptake and p38 MAPK activation in rodent native brain tissue, in human platelets and in cell lines in contrast to literature reports (Zhu et al.,2010). A different method was then used in which a release of cytokines was induced directly in the rat brain through an i.c.v. LPS treatment. Although proinflammatory cytokines involved in the change of animal mood, such as IL-1ß and TNFα, showed a significant increase in cortex and striatum, a modulation of SERT activity in term of Km and Vmax was not detected, confirming again that no interaction between cytokines, p38 MAP kinase and SERT function in vitro nor in vivo was evident. In contrast, this study revealed a positive interaction between 5HT7 receptors and p38 MAP kinase in glia cells. However, this pathway was not present in cortical neurons where 5HT7 receptors did not activate p38 MAP kinase but instead increased the AMPAR subunit, GluR1 and CREB phosphorylation. The effect on GluR1 was reversed by the specific 5HT7 antagonist, SB258719, and the PKA inhibitor, H89, confirming the specificity of response for 5HT7 receptors and the involvement of PKA in the mediation of GluR1 phosphorylation. In conclusion, this study displayed a lack of interaction between IL-1β and p38 MAP kinase on rat SERT while highlighting the effect of 5HT7 receptors on p38 MAP kinase, with different functions between glial and neuronal cells. Noteworthy, this is the first report that showed a positive interaction between 5HT7 receptors and AMPA which stimulates new investigation into the role of 5HT7 receptors in neuronal plasticity.
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