title: Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors.
abstract: 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. We propose that P2X4 receptors (P2X4Rs) regulate dopamine (DA) homeostasis and associated behaviors. Pre-synaptic and post-synaptic DA markers were significantly altered in the dorsal and ventral striatum of P2X4R KO mice, implicating altered DA neurotransmission. Sensorimotor gating deficits in P2X4R KO mice were rescued by DA antagonists. Ivermectin (IVM), a positive modulator of P2X4Rs, enhanced levodopa (L-DOPA)-induced motor behavior. These studies highlight potential interactions between P2X4Rs and DA system.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Khoja
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Damaris
authors.initials: D
authors.lastname: Garcia
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Asatryan
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jakowec
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA. ddavies@usc.edu.
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Davies
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D006706:Homeostasis / Q000235:genetics; D007398:Interpersonal Relations; D007559:Ivermectin / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D058848:Receptors, Purinergic P2X4 / Q000187:drug effects* / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D015259:Dopamine Agents; D058848:Receptors, Purinergic P2X4; D007980:Levodopa; D007559:Ivermectin; D016627:Oxidopamine; D004298:Dopamine
keywords: 6-OHDA; Ivermectin; P2X4 receptors; Parkinson's disease; dopamine receptors; schizophrenia