Abstract
Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6JRXFP3TM1/DGen) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.
Highlights
Alcohol use disorders (AUDs), like other substance use disorders, are characterised in part by recurrent, escalating alcohol use [1], and environmental triggers, including stressful life experiences, can elicit a state of persistent anxiety that promotes the development and maintenancePLOS ONE | DOI:10.1371/journal.pone.0122504 April 7, 2015Relaxin-3 and Stress-Related Alcohol Preference funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
We report that Rxfp3 KO mice markedly reduce preference for a 10% v/v ethanol solution following multiple stress exposures compared to wild-type (WT) littermates, an effect that once established was persistent
Reductions in total fluid intake were observed in WT and Rxfp3 KO mice across stress treatments. These studies demonstrate that Rxfp3 KO mice exhibit similar baseline alcohol preference to WT littermates, but after repeated exposure to acute stressors Rxfp3 KO mice reduced their alcohol preference, an effect not observed in WT mice
Summary
Alcohol use disorders (AUDs), like other substance use disorders, are characterised in part by recurrent, escalating alcohol use [1], and environmental triggers, including stressful life experiences, can elicit a state of persistent anxiety that promotes the development and maintenancePLOS ONE | DOI:10.1371/journal.pone.0122504 April 7, 2015Relaxin-3 and Stress-Related Alcohol Preference funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Alcohol use disorders (AUDs), like other substance use disorders, are characterised in part by recurrent, escalating alcohol use [1], and environmental triggers, including stressful life experiences, can elicit a state of persistent anxiety that promotes the development and maintenance. Relaxin-3 and Stress-Related Alcohol Preference funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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