Pharmacological insights into the role of P2X4 receptors in behavioural regulation: Lessons from ivermectin

Marco Bortolato, Megan M. Yardley, Sheraz Khoja, Sean C. Godar, Liana Asatryan, Deborah A. Finn, Ronald L. Alkana, Stan G. Louie, Daryl L. Davies

Research output: Contribution to journalArticle

26 Scopus citations

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 P2X4 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 P2X4 receptor in behavioural organization remains poorly investigated. To study the effects of P2X4 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 P2X4 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 P2X4 receptors may play a role in the regulation of sensorimotor gating.

Original languageEnglish (US)
Pages (from-to)1059-1070
Number of pages12
JournalInternational Journal of Neuropsychopharmacology
Volume16
Issue number5
DOIs
StatePublished - Jun 2013

Keywords

  • Anxiety
  • P2X purinergic receptors
  • depression
  • ivermectin
  • pre-pulse inhibition of the startle

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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    Bortolato, M., Yardley, M. M., Khoja, S., Godar, S. C., Asatryan, L., Finn, D. A., Alkana, R. L., Louie, S. G., & Davies, D. L. (2013). Pharmacological insights into the role of P2X4 receptors in behavioural regulation: Lessons from ivermectin. International Journal of Neuropsychopharmacology, 16(5), 1059-1070. https://doi.org/10.1017/S1461145712000909