AMPAkine CX516 alleviated chronic ethanol exposure-induced neurodegeneration and depressive-like behavior in mice.

Chronic ethanol exposure (CEE) is associated with greater neurodegenerative effects and an increased risk of depression disorder. The AMPAR is thought to be involved in depression and a reduction in its GluA1 subunit was observed in the mouse hippocampus after CEE. AMPAkines are positive allosteric modulators of the AMPA receptor and have improved depressive-like behavior. However, the role of AMPARs in CEE-induced depressive-like behavior is not clear. It is unclear whether AMPAkines, positive allosteric agonists of AMPARs, protect against ethanol-induced depression. We investigated the effects of CX516 on ethanol-induced depressive-like behavior in a mouse model. CX516 (5 mg/kg) administration alleviated 20% (m/V) ethanol-induced depressive-like behavior in mice. Furthermore, CX516 significantly diminished the inhibition of the ERK1/2-BDNF-TrkB pathway in the hippocampus of ethanol-exposed mice. In addition, CX516 attenuated the levels of pro-inflammatory (IL-6, IL-1β), apoptosis (BAX, BCL-2), and neurodegeneration (FJC) in the mouse hippocampus induced by CEE.