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

Gölöncsér, Flóra and Baranyi, Mária and Tod, Pál and Maácz, Fruzsina and Sperlágh, Beáta (2024) P2X7 receptor inhibition alleviates mania-like behavior independently of interleukin-1β. ISCIENCE, 27 (3). No.-109284. ISSN 2589-0042

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Abstract

Purinergic dysfunctions are associated with mania and depression pathogenesis. P2X7 receptor (P2X7R) mediates the IL-1b 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-1b. Treatment with JNJ-47965567, a P2X7R antagonist, abolished AMPH-induced hyperlocomotion in wild-type and IL-1a/b-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/b-gene deficiency, attenuated AMPH-induced [3H]dopamine release from striatal slices. In wild-type and IL-1a/b-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-1b.

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