LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence
Abstract Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KO...
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-56500-9 |
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| author | Francisco J. Flores-Ramirez Jessica M. Illenberger Glenn Pascasio Lars Terenius Rémi Martin-Fardon |
| author_facet | Francisco J. Flores-Ramirez Jessica M. Illenberger Glenn Pascasio Lars Terenius Rémi Martin-Fardon |
| author_sort | Francisco J. Flores-Ramirez |
| collection | DOAJ |
| description | Abstract Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD. |
| first_indexed | 2024-04-25T01:06:42Z |
| format | Article |
| id | doaj.art-0a3ecdaca62e4aa0bd3ed2bc0ace658e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-25T01:06:42Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0a3ecdaca62e4aa0bd3ed2bc0ace658e2024-03-10T12:10:12ZengNature PortfolioScientific Reports2045-23222024-03-0114111110.1038/s41598-024-56500-9LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependenceFrancisco J. Flores-Ramirez0Jessica M. Illenberger1Glenn Pascasio2Lars Terenius3Rémi Martin-Fardon4Department of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Clinical Neuroscience, Karolinska InstituteDepartment of Molecular Medicine, The Scripps Research InstituteAbstract Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.https://doi.org/10.1038/s41598-024-56500-9Alcohol use disorderDynorphinKappa-opioid receptor antagonistLY2444296 |
| spellingShingle | Francisco J. Flores-Ramirez Jessica M. Illenberger Glenn Pascasio Lars Terenius Rémi Martin-Fardon LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence Scientific Reports Alcohol use disorder Dynorphin Kappa-opioid receptor antagonist LY2444296 |
| title | LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence |
| title_full | LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence |
| title_fullStr | LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence |
| title_full_unstemmed | LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence |
| title_short | LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence |
| title_sort | ly2444296 a κ opioid receptor antagonist selectively reduces alcohol drinking in male and female wistar rats with a history of alcohol dependence |
| topic | Alcohol use disorder Dynorphin Kappa-opioid receptor antagonist LY2444296 |
| url | https://doi.org/10.1038/s41598-024-56500-9 |
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