Quetiapine as antidepressant: a putative cellular mechanism through ERK1/2 activation and induction of GDNF Release in C6 Glioma Cells

Quetiapine is an atypical antipsychotic which has been shown to possess also antidepressant efficacy in the treatment of bipolar and unipolar depression. Recently, it has been shown that a link between the activation of the ERK/MAPK signalling pathway and the release of GDNF appears to be a specific feature of antidepressants. To get a first insight into the putative molecular mechanism of action of quetiapine as an antidepressant, we examined its impact and that of its major metabolite norquetiapine on the activation of the ERK/MAPK signalling pathway in C6 glioma cells and we investigated the induction of GDNF release as a possible physiological consequence of this activation. Interestingly, we found that norquetiapine, similarly to the antidepressant reboxetine, activated both ERK1 and ERK2, which resulted in enhanced release of GDNF that was dependent on ERK/MAPK activation, as it could be significantly reversed by pre-treatment with a pharmacological inhibitor of ERK activation. In contrast, quetiapine induced activation of ERK2 only. It also caused release of GDNF, but this release was independent of ERK activation. Our results reveal the release of GDNF as a consequence of ERK/MAPK signalling activation by norquetiapine, which may contribute to the molecular antidepressant properties of quetiapine.