P2X7 receptor inhibition alleviates mania-like behavior independently of interleukin-1b

Purinergic dysfunctions are associated with mania and depression pathogenesis. P2X7 receptor (P2X7R) mediates the IL -10 maturation via NLRP3 inflammasome activation. We tested in a mouse model of the subchronic amphetamine (AMPH)-induced hyperactivity whether P2X7R inhibition alleviated mania -like behavior through IL -10. Treatment with JNJ-47965567, a P2X7R antagonist, abolished AMPH-induced hyperlocomotion in wild -type and IL -1a/0 -knockout male mice. The NLRP3 inhibitor MCC950 failed to reduce AMPH-induced locomotion in WT mice, whereas the IL -1 receptor antagonist anakinra slightly increased it. AMPH increased IL -10, TNF-a, and TBARS levels, but did not influence BDNF levels, serotonin, dopamine, and noradrenaline content in brain tissues in either genotypes. JNJ-47965567 and P2rx7-gene deficiency, but not IL -1a/0 -gene deficiency, attenuated AMPH-induced [3H]dopamine release from striatal slices. In wild -type and IL -1a/0 -knockout female mice, JNJ-47965567 was also effective in attenuating AMPHinduced hyperlocomotion. This study suggests that AMPH-induced hyperactivity is modulated by P2X7Rs, but not through IL -10.