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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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
Pages (from-to)2022-2031
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume39
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Purinergic P2X4 Receptors
Alcohol Drinking
Rats
Alcohols
Ivermectin
Ventral Tegmental Area
Small Interfering RNA
Sucrose
Antiparasitic Agents
Drinking Behavior
Lentivirus

Keywords

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

ASJC Scopus subject areas

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

Cite this

Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats. / Franklin, Kelle M.; Hauser, Sheketha R.; Lasek, Amy W.; Bell, Richard; Mcbride, William J.

In: Alcoholism: Clinical and Experimental Research, Vol. 39, No. 10, 01.10.2015, p. 2022-2031.

Research output: Contribution to journalArticle

Franklin, Kelle M. ; Hauser, Sheketha R. ; Lasek, Amy W. ; Bell, Richard ; Mcbride, William J. / Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats. In: Alcoholism: Clinical and Experimental Research. 2015 ; Vol. 39, No. 10. pp. 2022-2031.
@article{3bfceda2ddc74969a4ee6ee940aa7660,
title = "Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats",
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.",
keywords = "P2rx4, Alcohol Drinking, High-Alcohol-Drinking Rats, Ivermectin, P2X4 Receptor",
author = "Franklin, {Kelle M.} and Hauser, {Sheketha R.} and Lasek, {Amy W.} and Richard Bell and Mcbride, {William J.}",
year = "2015",
month = "10",
day = "1",
doi = "10.1111/acer.12836",
language = "English",
volume = "39",
pages = "2022--2031",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats

AU - Franklin, Kelle M.

AU - Hauser, Sheketha R.

AU - Lasek, Amy W.

AU - Bell, Richard

AU - Mcbride, William J.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - P2rx4

KW - Alcohol Drinking

KW - High-Alcohol-Drinking Rats

KW - Ivermectin

KW - P2X4 Receptor

UR - http://www.scopus.com/inward/record.url?scp=84943302609&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943302609&partnerID=8YFLogxK

U2 - 10.1111/acer.12836

DO - 10.1111/acer.12836

M3 - Article

C2 - 26334550

AN - SCOPUS:84943302609

VL - 39

SP - 2022

EP - 2031

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 10

ER -