In addition to the above

In addition to the above-mentioned synaptic mechanisms, the serotonergic system also has a critical role in the antidepressant effects of mGlu2/3 receptor antagonists. Indeed, we previously reported that mGlu2/3 receptor antagonists increased the firing rate of serotonin neurons in the dorsal raphe nucleus (DRN) (Kawashima et al., 2005), and also the extracellular serotonin concentrations in the medial prefrontal simvastatin zocor receptor (mPFC) (Karasawa et al., 2005; Kawashima et al., 2005), indicating that mGlu2/3 receptor antagonists enhance serotonergic transmission. The important role of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists has been demonstrated by the finding that depletion of serotonin by para-chlorophenylalanine treatment abolished the antidepressant effects of an mGlu2/3 receptor antagonist (Fukumoto et al., 2014, 2016). Interestingly, the serotonergic system has also been shown to have a role in the antidepressant actions of ketamine (du Jardin et al., 2016; Fukumoto et al., 2014, 2016; Gigliucci et al., 2013; Pham et al., 2017). Notably, the opposite findings have also been reported for both mGlu2/3 receptor antagonists (Pałucha-Poniewiera et al., 2010) and ketamine (Zhang et al., 2017), which may be ascribed to differences in the experimental conditions. However, the detailed mechanisms of involvement of the serotonergic system in the actions of either the mGlu2/3 receptor antagonists or ketamine still remain to be fully explored. We previously demonstrated involvement of the 5-HT1A receptor in the actions of an mGlu2/3 receptor antagonist and ketamine in mice, based on the results in the novelty-suppressed feeding test (NSFT) (Fukumoto et al., 2014). Moreover, we recently showed that selective stimulation of the 5-HT1A receptor and the consequent activation of phosphoinositide-3 kinase (PI3K)/Akt signaling in the mPFC has a critical role in the sustained antidepressant effect of ketamine (Fukumoto et al., 2018). These findings prompted us to investigate whether activation of PI3K/Akt signaling triggered by stimulation of the mPFC 5-HT1A receptor also has an important role in the sustained antidepressant effects of mGlu2/3 receptor antagonists. In the present study, we investigated the role of the 5-HT1A receptor in the mPFC and one of its downstream signaling pathways (PI3K/Akt signaling) in the antidepressant effect of LY341495, an mGlu2/3 receptor antagonist. PI3K/Akt signaling activates mechanistic target of rapamycin complex 1 (mTORC1) signaling to stimulate synaptogenesis (Duman et al., 2016; Hoeffer and Klann, 2010), and mTORC1 signaling has been implicated in the sustained antidepressant effect of LY341495 (Dwyer et al., 2012; Koike et al., 2011). Therefore, we also investigated the role of mTORC1 signaling in the mPFC in the antidepressant effect of LY341495 in this study. In addition, we investigated the involvement of the DRN neurons in the antidepressant effect of LY341495, because we found in the previous study that LY341495 activates subpopulations of the DRN 5-HT neurons through mPFC projections (Fukumoto et al., 2016).
Materials and methods
Results
Discussion In the present study, we demonstrated that stimulation of the mPFC 5-HT1A receptor and the consequent activation of PI3K/Akt signaling mediate the sustained antidepressant effect of LY341495, an mGlu2/3 receptor antagonist, in the FST. Moreover, we found that activation of mTORC1 signaling, a signaling pathway downstream of PI3K/Akt signaling, in the mPFC also has an important role in the sustained antidepressant effect of LY341495. These results suggest that stimulation of the mPFC 5-HT1A receptor and the consequent activation of the PI3K/Akt/mTORC1 signaling pathway, which has been implicated in synaptic plasticity, have critical roles in the sustained antidepressant effect of mGlu2/3 receptor antagonists. In a previous study, we demonstrated that the same mechanisms also have a critical role in the sustained antidepressant effect exerted by ketamine (Fukumoto et al., 2018); thus, these same pathways appear to mediate the sustained antidepressant effects of both mGlu2/3 receptor antagonists and ketamine.