Depression as a Neuroendocrine Disorder: Emerging Neuropsychopharmacological Approaches beyond Monoamines

Figure 2

Effects of ketamine on the glutamatergic synapse. Ketamine acts as an NMDA antagonist on GABAergic interneurons, as well as on postsynaptic glutamatergic neurons. Antagonism in the former results in disinhibition of presynaptic glutamatergic neurons, thus favoring activation of AMPAR in postsynaptic glutamatergic neurons. This, along with activation of voltage-dependent calcium channels, results in activation of the PI3K pathway which leads to increased mTOR activity. Furthermore, antagonism of NMDAR leads to inhibition of the nitric oxide pathway, which in turn leads to Rheb stabilization and mTOR pathway potentiation. mTOR increases p70s6K activity, which promotes BDNF signaling. BDNF activity is also favored by the inactivation of eEf2K secondary to NMDAR antagonism.