title: Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin.
abstract: Purinergic ionotropic P2X receptors are a family of cation-permeable channels that bind extracellular adenosine 5'-triphosphate. In particular, convergent lines of evidence have recently highlighted P2X(4) receptors as a potentially critical target in the regulation of multiple nervous and behavioural functions, including pain, neuroendocrine regulation and hippocampal plasticity. Nevertheless, the role of the P2X(4) receptor in behavioural organization remains poorly investigated. To study the effects of P2X(4) activation, we tested the acute effects of its potent positive allosteric modulator ivermectin (IVM, 2.5-10 mg/kg i.p.) on a broad set of paradigms capturing complementary aspects of perceptual, emotional and cognitive regulation in mice. In a novel open field, IVM did not induce significant changes in locomotor activity, but increased the time spent in the peripheral zone. In contrast, IVM produced anxiolytic-like effects in the elevated plus maze and marble burying tasks, as well as depression-like behaviours in the tail-suspension and forced swim tests. The agent induced no significant behavioural changes in the conditioned place preference test and in the novel object recognition task. Finally, the drug induced a dose-dependent decrease in sensorimotor gating, as assessed by pre-pulse inhibition (PPI) of the acoustic startle reflex. In P2X(4) knockout mice, the effects of IVM in the open field and elevated plus maze were similar to those observed in wild type mice; conversely, the drug significantly increased startle amplitude and failed to reduce PPI. Taken together, these results suggest that P2X(4) receptors may play a role in the regulation of sensorimotor gating.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.forename: Megan M
authors.initials: MM
authors.lastname: Yardley
authors.forename: Sheraz
authors.initials: S
authors.lastname: Khoja
authors.forename: Sean C
authors.initials: SC
authors.lastname: Godar
authors.forename: Liana
authors.initials: L
authors.lastname: Asatryan
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Finn
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Alkana
authors.forename: Stan G
authors.initials: SG
authors.lastname: Louie
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Davies
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension; D007306:Insecticides / Q000494:pharmacology*; D007559:Ivermectin / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D058848:Receptors, Purinergic P2X4 / Q000172:deficiency / Q000378:metabolism*; D055139:Sensory Gating / Q000187:drug effects; D018709:Statistics, Nonparametric; D013550:Swimming
chemical_list: D007306:Insecticides; D058848:Receptors, Purinergic P2X4; D007559:Ivermectin