Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity
IntroductionConsidering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in etha...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnbeh.2024.1498201/full |
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| author | Sara Faccidomo Sara Faccidomo Vallari R. Eastman Taruni S. Santanam Katarina S. Swaim Seth M. Taylor Clyde W. Hodge Clyde W. Hodge |
| author_facet | Sara Faccidomo Sara Faccidomo Vallari R. Eastman Taruni S. Santanam Katarina S. Swaim Seth M. Taylor Clyde W. Hodge Clyde W. Hodge |
| author_sort | Sara Faccidomo |
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| description | IntroductionConsidering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice.MethodsC57BL/6J mice (male and female) were assessed for EtOH intake under continuous and limited access conditions in the home cage. Acute sensitivity to EtOH sedation and blood clearance were evaluated as potential modifying factors. Motivation to consume EtOH was measured using operant self-administration procedures. Sex-specific differences in neural regulation of EtOH reinforcement were examined by testing the effects of a glutamate AMPA receptor antagonist on operant EtOH self-administration.ResultsFemale C57BL/6J mice exhibited a time-dependent escalation in EtOH intake under both continuous and limited access conditions. They were less sensitive to EtOH sedation and had lower blood levels post-EtOH administration (4 g/kg) despite similar clearance rates. Females also showed increased operant EtOH self-administration and progressive ratio performance over a 30-day baseline period compared to males. The AMPAR antagonist GYKI 52466 (0–10 mg/kg, IP) dose-dependently reduced EtOH-reinforced lever pressing in both sexes, with no differences in potency or efficacy.DiscussionThese findings confirm that female C57BL/6J mice consume more EtOH than males in home-cage conditions and exhibit reduced acute sedation, potentially contributing to higher EtOH intake. Females demonstrated increased operant EtOH self-administration and motivation, indicating higher reinforcing efficacy. The lack of sex differences in the relative effects of GYKI 52466 suggests that AMPAR activity is equally required for EtOH reinforcement in both sexes. |
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| id | doaj-art-a5b417419acc4d619bd2237b81d5d9c5 |
| institution | Kabale University |
| issn | 1662-5153 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj-art-a5b417419acc4d619bd2237b81d5d9c52025-01-22T07:11:20ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532025-01-011810.3389/fnbeh.2024.14982011498201Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activitySara Faccidomo0Sara Faccidomo1Vallari R. Eastman2Taruni S. Santanam3Katarina S. Swaim4Seth M. Taylor5Clyde W. Hodge6Clyde W. Hodge7Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesIntroductionConsidering sex as a biological variable (SABV) in preclinical research can enhance understanding of the neurobiology of alcohol use disorder (AUD). However, the behavioral and neural mechanisms underlying sex-specific differences remain unclear. This study aims to elucidate SABV in ethanol (EtOH) consumption by evaluating its reinforcing effects and regulation by glutamate AMPA receptor activity in male and female mice.MethodsC57BL/6J mice (male and female) were assessed for EtOH intake under continuous and limited access conditions in the home cage. Acute sensitivity to EtOH sedation and blood clearance were evaluated as potential modifying factors. Motivation to consume EtOH was measured using operant self-administration procedures. Sex-specific differences in neural regulation of EtOH reinforcement were examined by testing the effects of a glutamate AMPA receptor antagonist on operant EtOH self-administration.ResultsFemale C57BL/6J mice exhibited a time-dependent escalation in EtOH intake under both continuous and limited access conditions. They were less sensitive to EtOH sedation and had lower blood levels post-EtOH administration (4 g/kg) despite similar clearance rates. Females also showed increased operant EtOH self-administration and progressive ratio performance over a 30-day baseline period compared to males. The AMPAR antagonist GYKI 52466 (0–10 mg/kg, IP) dose-dependently reduced EtOH-reinforced lever pressing in both sexes, with no differences in potency or efficacy.DiscussionThese findings confirm that female C57BL/6J mice consume more EtOH than males in home-cage conditions and exhibit reduced acute sedation, potentially contributing to higher EtOH intake. Females demonstrated increased operant EtOH self-administration and motivation, indicating higher reinforcing efficacy. The lack of sex differences in the relative effects of GYKI 52466 suggests that AMPAR activity is equally required for EtOH reinforcement in both sexes.https://www.frontiersin.org/articles/10.3389/fnbeh.2024.1498201/fullsex as a biological variableethanolalcohol drinkingglutamateAMPA receptorsoperant self-administration |
| spellingShingle | Sara Faccidomo Sara Faccidomo Vallari R. Eastman Taruni S. Santanam Katarina S. Swaim Seth M. Taylor Clyde W. Hodge Clyde W. Hodge Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity Frontiers in Behavioral Neuroscience sex as a biological variable ethanol alcohol drinking glutamate AMPA receptors operant self-administration |
| title | Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity |
| title_full | Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity |
| title_fullStr | Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity |
| title_full_unstemmed | Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity |
| title_short | Distinct sex differences in ethanol consumption and operant self-administration in C57BL/6J mice with uniform regulation by glutamate AMPAR activity |
| title_sort | distinct sex differences in ethanol consumption and operant self administration in c57bl 6j mice with uniform regulation by glutamate ampar activity |
| topic | sex as a biological variable ethanol alcohol drinking glutamate AMPA receptors operant self-administration |
| url | https://www.frontiersin.org/articles/10.3389/fnbeh.2024.1498201/full |
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