The α7 nicotinic receptor positive allosteric modulator, PNU‐120596, reverses lipopolysaccharide‐induced depressive‐like behavior in mice

Abstract

Previous evidence indicates that neuroinflammation plays a critical role in the pathophysiology of major depressive disorder (MDD) involving microglial α7 nicotinic acetylcholine receptors (nAChRs). The objective of the present study was to determine the effects of PNU‐120596, an α7 nAChR positive allosteric modulator (PAM), on depressive‐like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba‐1), microglial marker, in mice following lipopolysaccharide (LPS) administration, an animal model for depressive‐like behavior. Forced swim test (FST) and tail suspension test (TST) were used to determine the effects of PNU‐120596 on depressive‐like behavior. We also examined the effects of PNU‐120596 on Iba‐1 expression by using Western blot analysis and immunofluorescence staining in the hippocampus and prefrontal cortex, brain regions implicated in MDD. Administration of LPS (1 mg/kg, i.p.) significantly increased immobility time during FST and TST. The PNU‐120596 (1 or 4 mg/kg, i.p.) dose‐dependently decreased the LPS‐induced immobility time during FST and TST. Similarly, the PNU‐120596 (4 mg/kg, i.p.) significantly decreased the LPS‐induced increased Iba‐1 expression in the hippocampus and prefrontal cortex. In conclusion, these results suggest that PNU‐120596 reduces LPS‐induced depressive‐like behavior likely by targeting microglial α7 nAChRs in the hippocampus and prefrontal cortex in mice. Therefore, α7 nAChR PAMs could be developed as potential therapeutic utility for the treatment of MDD in humans.Support or Funding InformationSupported in part by grant from Saudi Arabian Cultural Mission, USAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.