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

Flóra Gölöncsér; Mária Baranyi; Pál Tod; Fruzsina Maácz; Beáta Sperlágh

doi:10.1016/j.isci.2024.109284

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

iScience. 2024 Feb 20;27(3):109284. doi: 10.1016/j.isci.2024.109284. eCollection 2024 Mar 15.

Authors

Flóra Gölöncsér¹, Mária Baranyi¹, Pál Tod¹, Fruzsina Maácz^{1

2}, Beáta Sperlágh^{1

2}

Affiliations

¹ Laboratory of Molecular Pharmacology, HUN-REN Institute of Experimental Medicine, 1083 Budapest, Hungary.
² János Szentágothai School of Neurosciences, Semmelweis University School of Ph.D Studies, 1083 Budapest, Hungary.

Abstract

Purinergic dysfunctions are associated with mania and depression pathogenesis. P2X7 receptor (P2X7R) mediates the IL-1β 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-1β. Treatment with JNJ-47965567, a P2X7R antagonist, abolished AMPH-induced hyperlocomotion in wild-type and IL-1α/β-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-α, 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-1α/β-gene deficiency, attenuated AMPH-induced [³H]dopamine release from striatal slices. In wild-type and IL-1α/β-knockout female mice, JNJ-47965567 was also effective in attenuating AMPH-induced hyperlocomotion. This study suggests that AMPH-induced hyperactivity is modulated by P2X7Rs, but not through IL-1β.

Keywords: Behavioral neuroscience; Biological sciences; Natural sciences; Neuroscience; Pharmacology.