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Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High‐Alcohol‐Drinking (HAD) Rats
Author(s) -
Franklin Kelle M.,
Hauser Sheketha R.,
Lasek Amy W.,
Bell Richard L.,
McBride William J.
Publication year - 2015
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12836
Subject(s) - alcohol , ethanol , ivermectin , ventral tegmental area , self administration , pharmacology , purinergic receptor , receptor , alcohol intake , chemistry , endocrinology , medicine , biochemistry , dopamine , dopaminergic , veterinary medicine
Background The P2X4 receptor (P2X4R) is thought to be involved in regulating alcohol‐consuming behaviors, and ethanol (Et OH ) 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 RNA s (sh RNA s) targeting P2rx4 on Et OH 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% Et OH versus water. Dose–response effects of ivermectin (1.5 to 7.5 mg/kg, intraperitoneally [i.p.]) on Et OH 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% Et OH under 2‐hour limited access conditions, and dose–response effects of intracerebroventricular ( ICV ) administration of ivermectin (0.5 to 2.0 μ g) were determined over 5 consecutive days. The third experiment determined the effects of microinfusion of a lentivirus expressing P2rx4 sh RNA s into the posterior ventral tegmental area ( VTA ) on 24‐hour Et OH 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 Et OH intake (~20%). Conclusions Overall, the results of this study support a role for P2X4Rs within the mesolimbic system in mediating alcohol‐drinking behavior.