Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats
| Autor: | Richard L. Bell, Kelle M. Franklin, Sheketha R. Hauser, Amy W. Lasek, William J. McBride |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Alcohol Drinking Purinergic P2X Receptor Antagonists Medicine (miscellaneous) Alcohol Pharmacology Toxicology Article Purinergic P2X Receptor Agonists chemistry.chemical_compound Ivermectin Internal medicine medicine Animals RNA Small Interfering Receptor Ethanol Dose-Response Relationship Drug business.industry Ventral Tegmental Area Purinergic receptor Rats Inbred Strains Antiparasitic agent Rats P2RX4 Ventral tegmental area Psychiatry and Mental health Infusions Intraventricular Endocrinology medicine.anatomical_structure chemistry Female business Receptors Purinergic P2X4 medicine.drug |
| Zdroj: | Alcoholism: Clinical and Experimental Research. 39:2022-2031 |
| ISSN: | 0145-6008 |
| Popis: | 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 7.5 mg/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 2.0 μg) 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. |
| Databáze: | OpenAIRE |
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