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Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors

Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ion channels regulated by ATP. We recently demonstrated that P2X4R knockout (KO) mice exhibited deficits in sensorimotor gating, social interaction, and ethanol drinking behavior. Dopamine (DA) dysfunction may underlie these behavioral changes, but there is no direct evidence for P2X4Rs’ role in DA neurotransmission. To test this hypothesis, we measured markers of DA function and dependent behaviors in P2X4R KO mice. P2X4R KO mice exhibited altered density of pre‐synaptic markers including tyrosine hydroxylase, dopamine transporter; post‐synaptic markers including dopamine receptors and phosphorylation of downstream targets including dopamine and cyclic‐AMP regulated phosphoprotein of 32 kDa and cyclic‐AMP‐response element binding protein in different parts of the striatum. Ivermectin, an allosteric modulator of P2X4Rs, significantly affected dopamine and cyclic AMP regulated phosphoprotein of 32 kDa and extracellular regulated kinase1/2 phosphorylation in the striatum. Sensorimotor gating deficits in P2X4R KO mice were rescued by DA antagonists. Using the 6‐hydroxydopamine model of DA depletion, P2X4R KO mice exhibited an attenuated levodopa (L‐DOPA)‐induced motor behavior, whereas ivermectin enhanced this behavior. Collectively, these findings identified an important role for P2X4Rs in maintaining DA homeostasis and illustrate how this association is important for CNS functions including motor control and sensorimotor gating.