Positive Allosteric Modulation of AMPAR by PF-4778574 Produced Rapid Onset Antidepressant Actions in Mice

: It has been reported that fast-acting antidepressants enhance glutamatergic neurotransmission in the prefrontal cortex (PFC) regions via alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation. However, the precise mechanisms underlying the fast-acting antidepressants lead to an activation of AMPAR pathways remain largely unclear. To address this issue, a novel AMPAR positive allosteric agonist, PF-4778574, was used to test the rapid effects and the role of VGF (nonacronymic)/brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/AKT signaling in these actions in mice. We found that PF-4778574 rapidly alleviated chronic unpredictable stress-induced depression-like behaviors in a concentration-dependent manner. In addition, knock down of vesicular glutamate transporter 1 (VGLUT1) in the PFC of mice induced depression-like behaviors, whereas treatment with PF-4778574 was sufficient to alleviate it, indicating a presynaptic VGLUT1 independent effect. Furthermore, we demonstrate that pharmacological inhibitors of AMPAR or of L-type voltage-dependent Ca2+ channel (L-VDCC) blocked the antidepressants' effect on behaviors and the upregulation on the AMPAR-mediated VGF/BDNF/TrkB/AKT signaling of PF-4778574. Together, our findings indicate that postsynaptic AMPAR activation followed by activation of L-VDCC and subsequent VGF/BDNF/TrkB/AKT signaling are required for the rapid antidepressant effects of PF-4778574. Our data support a promising therapeutic profile for PF-4778574 as a new fast-acting antidepressant.