Sex Differences in Binge‐Like and Aversion‐Resistant Alcohol Drinking in C57<scp>BL</scp>/6J Mice

Sneddon, Elizabeth A.; White, Robert D.; Radke, Anna K.

doi:10.1111/acer.13923

Cited by 123 publications

(127 citation statements)

References 53 publications

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“…These observations are consistent with previously reported findings with mouse DID models using other delivery vehicles and paradigms (Lyons et al, 2008;Moore et al, 2010;Rhodes et al, 2007). Moreover, female mice in the study consumed significantly greater quantities of EtOH than male mice during each DID episode (Figs 2 and 3), a phenomenon consistent with that reported by Crabbe and others (Crabbe et al, 2009;Rhodes et al, 2005;Sneddon et al, 2019).…”

Section: Sex-specific Difference In Binge Etoh Intakesupporting

confidence: 93%

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

Rath

Guergues

Pinho

et al. 2020

Alcoholism Clin & Exp Res

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Background Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward. However, the microglial molecular and cellular pathways associated with EtOH binge consumption remain poorly understood. Method In this study, adult C57BL/6J male and female mice were subjected daily to a gelatin‐based drinking‐in‐the‐dark voluntary EtOH consumption paradigm (3 h/d for 4 months) to characterize EtOH consumption and withdrawal‐associated and anxiety‐like behaviors. Brain microglia were isolated at the end and analyzed for protein expression profile changes using unbiased mass spectrometry‐based proteomic analysis. Results Both male and female mice consistently consumed binge quantities of EtOH daily, resulting in blood EtOH levels > 80 mg/dl measured at the end of the 3‐hour daily consumption period. Although female mice consumed a significantly greater amount of EtOH than male mice, EtOH withdrawal‐associated anxiety‐like behaviors measured by marble‐burying, light‐dark box, and elevated plus maze tests were predominantly observed in male mice. Proteomic analysis of microglia isolated from the brains of animals at the end of the 4‐month binge EtOH consumption identified 117 and 37 proteins that were significantly up‐ or downregulated in EtOH‐exposed male and female mice, respectively, compared to their pair‐fed controls. Protein expression profile‐based pathway analysis identified several cellular pathways that may underlie the sex‐specific and EtOH withdrawal‐associated behavioral abnormalities. Conclusion Taken together, our findings revealed sex‐specific changes in EtOH withdrawal‐associated behaviors and signaling pathways in the mouse brain microglia and may help advance our understanding of the molecular, cellular, and behavioral changes related to human binge EtOH consumption.

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Section: Sex-specific Difference In Binge Etoh Intakesupporting

confidence: 93%

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

Rath

Guergues

Pinho

et al. 2020

Alcoholism Clin & Exp Res

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“…Sex differences in alcohol intake and preference are well recognized in animals and humans, with females generally drink more alcohol than males [30][31][32][53][54][55]. Consistent with this, average daily alcohol intake in female Bmal1CTR mice was significantly greater than in Bmal1CTR males (P<0.0001, unpaired two-tailed t test) and mean alcohol preference was significantly higher in Bmal1CTR females than Bmal1CTR males (P<0.05, unpaired two-tailed t test) ( Supplementary Fig.…”

Section: Deletion Of Bmal1 or Per2 From Msns Eliminates Sex Differencsupporting

confidence: 66%

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Zavalía¹,

Schöttner²,

Goldsmith³

et al. 2020

Preprint

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SummaryThe clock gene Bmal1 plays an obligatory role in the generation of circadian rhythms in gene expression, physiology, and behavior in mammals [1–4]. In mice, perturbations in Bmal1 expression in the brain are associated with loss of circadian rhythmicity and various physiological and behavioral disturbances, including disrupted sleep architecture and deficits in cognitive and affective behaviors [5–14]. Gene association studies in both humans and animals suggest that Bmal1 may also play a role in the control of appetitive behaviors such as alcohol preference and consumption [15–19]. Although there is evidence that genes that interact with Bmal1 in the molecular circadian clock, such as Per2 and Clock influence alcohol intake and preference [15, 20–23], experimental evidence of a causal role of Bmal1 is lacking. In addition, the specific brain regions where Bmal1 might affect alcohol consumption are not known. We investigated voluntary alcohol consumption in conditional knockout mice that lack BMAL1 protein exclusively in the striatum, which is an important structure in the control of alcohol intake and preference [24–29]. Particular emphasis was attributed to the investigation of male and female mice because of known sex differences in alcohol intake and preference [30–32], and the impact of a sexually dimorphic constitution of circadian clocks on behavior [33, 34]. We found that deletion of BMAL1 from the principal medium spiny neurons (MSNs) of the striatum significantly altered voluntary alcohol intake and preference, without affecting total fluid intake, sucrose preference, body weight, or circadian rhythms in behavior. Strikingly, there were major sex differences in the effect of striatal BMAL1 deletion on alcohol consumption. While striatal BMAL1 deletion augmented alcohol intake and preference in males, the same deletion suppressed intake and preference in females. Interestingly, striatal deletion of PER2, a clock gene that interacts with Bmal1 in the circadian clock, and which has been shown to limit alcohol consumption in mice [22], mimicked the effect of striatal BMAL1 deletion, albeit only in males. Together, our results reveal that BMAL1 in MSNs of the striatum plays a sexually dimorphic role in the control of alcohol intake in mice, restraining consumption in males, possibly by interacting with PER2, and promoting intake in females, independently of PER2. We therefore hypothesize that a sex-specific mechanism in the function of BMAL1 in MSNs of the striatum regulates differences between male and female mice in the propensity to consume alcohol.

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“…As self‐administration is known to induce distinct patterns of behavior and neurobiological alterations when compared to experimenter administered drugs and alcohol, (McFarland et al., , ; Moolten and Kornetsky, ; Robinson et al., ), this may explain some of the discrepancies observed between these studies. Relatedly, the findings indicating a lack of sex differences in consumption of quinine‐adulterated EtOH were in mice that exclusively self‐administered alcohol (Sneddon et al., ). It is possible that the sex differences observed in our findings in part result from experimenter administration of EtOH and/or restriction to the rewarding effects of postingestive EtOH.…”

Section: Discussionmentioning

confidence: 99%

“…Research investigating compulsive‐like EtOH seeking includes a number of models, involving punished operant self‐administration and consumption of quinine‐adulterated EtOH (Darevsky et al., ; Hopf and Lesscher, ; Radke et al., ). Recent research has identified similar sensitivities to quinine adulteration in males and females, suggesting that sex differences are not present in this form of inflexible EtOH taking (Sneddon et al., ). Importantly, in both punished self‐administration and quinine adulteration models, the experience of reward and aversion is occurring as the animal makes the decision whether to continue consuming or seeking EtOH.…”

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confidence: 99%

Sex Differences in Ethanol Reward Seeking Under Conflict in Mice

Xie

Buck

Bryant

et al. 2019

Alcoholism Clin & Exp Res

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Background: Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present.Methods: To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "salinepaired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock.Results: Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber.Conclusions: Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward-and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.

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Sex Differences in Binge‐Like and Aversion‐Resistant Alcohol Drinking in C57BL/6J Mice

Cited by 123 publications

References 53 publications

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

Chronic Voluntary Binge Ethanol Consumption Causes Sex‐Specific Differences in Microglial Signaling Pathways and Withdrawal‐associated Behaviors in Mice

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Sex Differences in Ethanol Reward Seeking Under Conflict in Mice

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