NLRP3 deficiency decreases alcohol intake controlling anxiety-like behavior via modification of glutamatergic transmission in mPFC-striatal circuits

Abstract

Background Repeated binge alcohol drinking and chronic alcohol consumption with negative effects such as anxiety on cessation induces alcohol use disorders. This process is associated with activation of NLRP3 inflammasome-mediated responses. However, whether and how inhibition of NLRP3 inflammasome alters alcohol intake and anxiety behavior remains unclear. Methods A combination of drinking-in-the dark and Gavage model were established in NLRP3-knockout and their control mice. Behaviors were assessed by open-field and elevated plus maze tests. Binge alcohol drinking at 2h and 4h were measured and 24 voluntary drinking was determined by a two-bottle choice paradigm. Western blot and ELISA were applied to examine the levels of NLRP3 inflammasome and inflammatory factors such as IL-1β and TNF-α. Nissl’s staining was measured the neuronal injury. Electrophysiological method was determined the glutamatergic transmission in mPFC to striatum circuits. In vivo opotogenetic LTP and LTD were applied to control the function of mPFC-striatal circuits on behavior of mice. MCC950 was used to antagonize NLRP3 inflammasome. Results The binge alcohol intake was decreased in NLRP3 KO mice compared to their control drinking mice. During alcohol withdrawal, NLRP3 deficiency attenuated anxiety-like behaviors and neuronal injury in mPFC and striatum. Moreover, we discovered that the glutamatergic transmission from cortex to striatum was reduced in NLRP3 KO mice. Importantly, in vivo optogenetic induction of long-term potentiation (LTP) of mPFC-striatal circuits reversed the effects of NLRP3 deficiency on glutamatergic transmission and anxiety behaviors. We also demonstrated that optogenetic induction of LTD decreased anxiety-like behaviors with a reduction of glutamatergic transmission. Interestingly, NLRP3 deficiency or inhibition (MCC950 injection)-mediated the attenuation of anxiety behavior reduced binge alcohol intake, but did not decrease 24h-voluntary alcohol consumption and alcohol preference. Conclusion Our results demonstrate that NLRP3 deficiency decreases binge alcohol intake and anxiety-like behaviors through downregulation of glutamatergic transmission in mPFC-striatal circuits, which may provide an anti-inflammatory target to treat alcohol use disorders.