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

Area of Science:

• Neuroscience
• Psychiatry
• Immunology

Background:

• Purinergic signaling, particularly via the P2X7 receptor (P2X7R), is implicated in the pathogenesis of mood disorders like mania and depression.
• P2X7R activation is known to mediate the maturation of interleukin-1 beta (IL-1β) through the NLRP3 inflammasome pathway.

Purpose of the Study:

• To investigate whether P2X7R inhibition could alleviate mania-like behaviors in a mouse model of subchronic amphetamine (AMPH)-induced hyperactivity.
• To determine if any observed behavioral effects were mediated through the IL-1β pathway.

Main Methods:

• Utilized a mouse model of subchronic amphetamine (AMPH) administration to induce hyperactivity.
• Administered JNJ-47965567, a selective P2X7R antagonist, and MCC950, an NLRP3 inhibitor, to assess their effects on AMPH-induced behaviors.
• Measured IL-1β levels, neurotransmitter content, and dopamine release in brain tissues.
• Tested effects in wild-type (WT) and IL-1α/β-knockout mice, as well as in both male and female mice.

Main Results:

• P2X7R antagonist JNJ-47965567 abolished AMPH-induced hyperlocomotion in both male and female WT and IL-1α/β-knockout mice.
• The NLRP3 inhibitor MCC950 did not reduce AMPH-induced locomotion, and the IL-1 receptor antagonist anakinra slightly increased it.
• AMPH administration increased IL-10, TNF-α, and TBARS levels but did not affect BDNF, serotonin, dopamine, or noradrenaline levels.
• P2X7R antagonism and P2rx7 gene deficiency, but not IL-1α/β gene deficiency, attenuated AMPH-induced [³H]dopamine release from striatal slices.

Conclusions:

• AMPH-induced hyperactivity in mice is modulated by P2X7 receptors.
• The modulatory effect of P2X7R on AMPH-induced hyperactivity does not appear to be mediated through the IL-1β pathway.
• P2X7R antagonism represents a potential therapeutic strategy for mania-like behaviors, independent of IL-1β signaling.