Effects of α7 nicotinic receptor positive allosteric modulator PNU120596 on microglial quinolinic acid formation following LPS‐induced depressive‐like behavior in mice

Abstract

Positive allosteric modulation of α7 nicotinic acetylcholine receptor (α7 nAChR) plays a critical role in regulating the neuroinflammation and microglial activation associated with major depressive disorder (MDD). Microglial quinolinic acid (QUIN), an N-methyl-D-aspartate (NMDA) receptor agonist, which is synthesized by 3-hydroxyanthranilic acid dioxygenase (HAAO) plays a critical role in the development of MDD-related symptoms. However, the role of α7 nAChR via allosteric modulation on QUIN formation in the brain in lipopolysaccharide (LPS)-induced depressive-like behavior is not known. Here, we have determined the effects of PNU120596, an α7 nAChR positive allosteric modulator, on HAAO expression and QUIN formation in the hippocampus and prefrontal cortex. We also examined the pharmacological interaction between PNU120596 and memantine, an NMDA receptor antagonist, on LPS-induced cognitive deficit and depressive-like behaviors. Immunofluorescence assay and real-time polymerase chain reaction were used to determine bionomical alteration, whereas Y-maze, tail suspension test (TST), and forced swim test (FST) were used to evaluate behavioral changes. LPS administration (1 mg/kg, i.p.) resulted in increased HAAO expression and QUIN formation in the hippocampus and prefrontal cortex. Pretreatment of PNU120596 (4 mg/kg, i.p.) reduced LPS-induced increase in HAAO expression and QUIN formation in these brain regions. Subthreshold dose of memantine (1 mg/kg, i.p.) enhanced the PNU120596 effects against LPS-induced cognitive deficit and depressive-like behaviors. Taken together, these results indicate that the antidepressant-like effects of PNU120596 are mediated by attenuation of LPS-induced QUIN formation in these brain regions. Therefore, α7 nAChR PAM could be a potential therapeutic utility for MDD associated with neurotoxic glutamatergic transmission.