Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats

Kelle M. Franklin, Sheketha R. Hauser, Amy W. Lasek, Richard L. Bell, William J. Mcbride

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Background: The P2X4 receptor (P2X4R) is thought to be involved in regulating alcohol-consuming behaviors, and ethanol (EtOH) has been reported to inhibit P2X4Rs. Ivermectin is an antiparasitic agent that acts as a positive allosteric modulator of the P2X4R. This study examined the effects of systemically and centrally administered ivermectin on alcohol drinking of replicate lines of high-alcohol-drinking (HAD-1/HAD-2) rats, and the effects of lentiviral-delivered short-hairpin RNAs (shRNAs) targeting P2rx4 on EtOH intake of female HAD-2 rats. Methods: For the first experiment, adult male HAD-1 and HAD-2 rats were given 24-hour free-choice access to 15% EtOH versus water. Dose-response effects of ivermectin (1.5 to 7.5mg/kg, intraperitoneally [i.p.]) on EtOH intake were determined; the effects of ivermectin were then examined for 2% w/v sucrose intake over 5 consecutive days. In the second experiment, female HAD-2 rats were trained to consume 15% EtOH under 2-hour limited access conditions, and dose-response effects of intracerebroventricular (ICV) administration of ivermectin (0.5 to 2.0μg) were determined over 5 consecutive days. The third experiment determined the effects of microinfusion of a lentivirus expressing P2rx4 shRNAs into the posterior ventral tegmental area (VTA) on 24-hour EtOH free-choice drinking of female HAD-2 rats. Results: The highest i.p. dose of ivermectin reduced alcohol drinking (30 to 45%) in both rat lines, but did not alter sucrose intake. HAD-2 rats appeared to be more sensitive than HAD-1 rats to the effects of ivermectin. ICV administration of ivermectin reduced 2-hour limited access intake (~35%) of female HAD-2 rats; knockdown of P2rx4 expression in the posterior VTA reduced 24-hour free-choice EtOH intake (~20%). Conclusions: Overall, the results of this study support a role for P2X4Rs within the mesolimbic system in mediating alcohol-drinking behavior.

Original languageEnglish (US)
Pages (from-to)2022-2031
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume39
Issue number10
DOIs
StatePublished - Oct 2015

Keywords

  • P2rx4
  • Alcohol Drinking
  • High-Alcohol-Drinking Rats
  • Ivermectin
  • P2X4 Receptor

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

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