Pharmacological insights into the role of P2X4 receptors in behavioral regulation: lessons from ivermectin
Identifieur interne : 002352 ( Ncbi/Merge ); précédent : 002351; suivant : 002353Pharmacological insights into the role of P2X4 receptors in behavioral regulation: lessons from ivermectin
Auteurs : Marco Bortolato [États-Unis] ; Megan Yardley [États-Unis] ; Sheraz Khoja [États-Unis] ; Sean C. Godar [États-Unis] ; Liana Asatryan [États-Unis] ; Deborah A. Finn [États-Unis] ; Ronald L. Alkana [États-Unis] ; Stan G. Louie [États-Unis] ; Daryl L. Davies [États-Unis]Source :
- The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) [ 1461-1457 ] ; 2012.
Abstract
Purinergic ionotropic P2X receptors are a family of cation-permeable channels that bind extracellular adenosine 5′-triphosphate (ATP). In particular, convergent lines of evidence have recently highlighted P2X4 receptors as a potentially critical target in the regulation of multiple nervous and behavioral functions, including pain, neuroendocrine regulation and hippocampal plasticity. Nevertheless, the role of the P2X4 receptor in behavioral 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 behaviors in the tail-suspension and forced swim tests. The agent induced no significant behavioral 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 prepulse 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.
Url:
DOI: 10.1017/S1461145712000909
PubMed: 23174033
PubMed Central: 3593990
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<front><div type="abstract" xml:lang="en"><p id="P1">Purinergic ionotropic P2X receptors are a family of cation-permeable channels that bind extracellular adenosine 5′-triphosphate (ATP). In particular, convergent lines of evidence have recently highlighted P2X4 receptors as a potentially critical target in the regulation of multiple nervous and behavioral functions, including pain, neuroendocrine regulation and hippocampal plasticity. Nevertheless, the role of the P2X4 receptor in behavioral 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 behaviors in the tail-suspension and forced swim tests. The agent induced no significant behavioral 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 prepulse 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.</p>
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Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033</aff>
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Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033</aff>
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Portland Alcohol Research Center, VA Medical Research, Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA</aff>
<author-notes><corresp id="FN1">Corresponding author: Daryl L. Davies, PhD, Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics & Policy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, Phone: (323) 442-1427, Fax: (323) 442-1704, <email>ddavies@usc.edu</email>
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<abstract><p id="P1">Purinergic ionotropic P2X receptors are a family of cation-permeable channels that bind extracellular adenosine 5′-triphosphate (ATP). In particular, convergent lines of evidence have recently highlighted P2X4 receptors as a potentially critical target in the regulation of multiple nervous and behavioral functions, including pain, neuroendocrine regulation and hippocampal plasticity. Nevertheless, the role of the P2X4 receptor in behavioral 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 behaviors in the tail-suspension and forced swim tests. The agent induced no significant behavioral 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 prepulse 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.</p>
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