Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine

Abstract

Numerous studies have demonstrated the antidepressant effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists in various rodent models. Importantly, it has been shown that the antidepressant effects of mGlu2/3 receptor antagonists in rodent models are similar to those of ketamine, which exerts rapid and long-lasting antidepressant effects in patients with major depressive disorders, including patients with treatment-resistant depression. In addition, the synaptic mechanisms underlying the effects of mGlu2/3 receptor antagonists are reported to be similar to those underlying the effects of ketamine. The roles of the serotonergic system in the antidepressant effects of mGlu2/3 receptor antagonists have recently been demonstrated. Moreover, it was investigated how mGlu2/3 receptor antagonists interact with the serotonergic system to exert antidepressant effects. Notably, the same neural mechanisms as those underlying the effects of ketamine may be involved in the antidepressant actions of the mGlu2/3 receptor antagonists. In this review, we shall summarize the antidepressant potential of mGlu2/3 receptor antagonists and their mechanisms of action in comparison with those of ketamine. In particular, we shall focus on the roles of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists.

Keywords: 5-HT1A receptor; AMPA receptor; antidepressant; ketamine; mGlu2/3 receptor antagonist; medial prefrontal cortex; serotonin.

Figure 1

Proposed serotonergic mechanisms through which mGlu2/3 receptor antagonists and ketamine exert their antidepressant effects. Both mGlu2/3 receptor antagonists and ketamine increase 5-HT release in the medial prefrontal cortex (mPFC) through activation of 5-HT neurons in the dorsal raphe nucleus (DRN). There are two hypotheses by which mGlu2/3 receptor antagonists and ketamine activate 5-HT neurons in the DRN. (1) mGlu2/3 receptor antagonists and ketamine activate neurons in the mPFC projecting to 5-HT neurons in the DRN. Stimulation of AMPA receptor both in the mPFC (to activate neurons projecting to the DRN) and in the DRN (to activate 5-HT neurons) may be involved in this pathway. mGlu2/3 receptor antagonists and ketamine indirectly stimulate AMPA receptor by increasing glutamate release in different manners. (2) Ketamine activates cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg), projecting to the DRN neurons where α4β2 nicotinic receptor, together with AMPA receptor, activates 5-HT neurons. Activation of 5-HT neurons in the DRN leads to increase in 5-HT release in the mPFC, and stimulates postsynaptic 5-HT_1A receptor.

Figure 2

Proposed 5-HT_1A receptor-mediated signaling pathway through which mGlu2/3 receptor antagonists and ketamine exert their antidepressant effects. 5-HT release induced by mGlu2/3 receptor antagonists and ketamine as described in Figure 1 stimulates postsynaptic 5-HT_1A receptor in the medial prefrontal cortex (mPFC). 5-HT_1A receptor stimulation activates phosphoinositide-3-kinase (PI3K) and subsequently Akt, leading to activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 signaling increased synthesis of synaptic proteins such as GluA1 and PSD95, which induces synaptic plasticity. Increase in GluA1 synthesis persistently activates AMPA receptor transmission, which may also be involved in sustained antidepressant effects of mGlu2/3 receptor antagonists and ketamine.