Sex Differences in Motivation to Self‐Administer Alcohol After 2 Weeks of Abstinence in Young‐Adult Heavy Drinkers

Plawecki, Martin H.; White, Kurt; Kosobud, Ann; Grahame, Nicholas J.; Zimmermann, U.; Crabb, David W.; O’Connor, Sean

doi:10.1111/acer.13860

Cited by 18 publications

(16 citation statements)

References 84 publications

(84 reference statements)

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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: 67%

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

confidence: 67%

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

Zavalía¹,

Schöttner²,

Goldsmith³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In humans, a progressive ratio trial of intravenous alcohol self-administration showed that women increased their work effort to obtain alcohol after resumption following 2 weeks of abstinence, whereas men decreased this effort. 113 Male rats exposed to alcohol vapors to produce dependence display increased compulsive-like behavior and increased intake on both fixed and progressive ratio schedules. 88 However, progressive ratio tests in Long Evans rats suggest there is no sex difference in motivation for alcohol, at least following extinction and reinstatement of alcohol self-administration.…”

Section: Preoccupation/anticipation Stagementioning

confidence: 99%

Sex Differences in the Neurobiology of Alcohol Use Disorder

Flores‐Bonilla

Richardson

2020

ARCR

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Sex differences may play a critical role in modulating how chronic or heavy alcohol use impacts the brain to cause the development of alcohol use disorder (AUD). AUD is a multifaceted and complex disorder driven by changes in key neurobiological structures that regulate executive function, memory, and stress. A three-stage framework of addiction (binge/intoxication; withdrawal/negative affect; preoccupation/anticipation) has been useful for conceptualizing the complexities of AUD and other addictions. Initially, alcohol drinking causes short-term effects that involve signaling mediated by several neurotransmitter systems such as dopamine, corticotropin releasing factor, and glutamate. With continued intoxication, alcohol leads to dysfunctional behaviors that are thought to be due in part to alterations of these and other neurotransmitter systems, along with alterations in neural pathways connecting prefrontal and limbic structures. Using the three-stage framework, this review highlights examples of research examining sex differences in drinking and differential modulation of neural systems contributing to the development of AUD. New insights addressing the role of sex differences in AUD are advancing the field forward by uncovering the complex interactions that mediate vulnerability.

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“…Free access to alcohol rewards is available for a prescribed period of time (usually 2 to 3 hours), with maximum BrAC levels allowed up to a predetermined safety limit. Because there is good accuracy of achieving the target BrAC, maximum allowable BrAC levels range up to 200 mg/dl, although most infusion self‐administration studies set the limit between 100 and 180 mg/dl (e.g., Plawecki et al, 2018b; Stangl et al, 2017; VanderVeen et al, 2016).…”

Section: Comparing and Contrasting Paradigmsmentioning

confidence: 99%

“…The literature associating intravenous alcohol self‐administration paradigms with behavioral and clinical phenotypes is emerging. Intravenous alcohol self‐administration has been associated with family history of alcoholism (Zimmermann et al, 2009), drinking history (Bujarski et al, 2018; Stangl et al, 2017), including binge drinking (Sloan et al, 2019), AUD risk (Gowin et al, 2017), craving (Green et al, 2019; Wardell et al, 2015), personality traits (Stangl et al, 2017; VanderVeen et al, 2016), sex differences (Cyders et al, 2016; Plawecki et al, 2018b), pharmacologic targets or interventions (Suchankova et al, 2017), and risk genotypes (Hendershot et al, 2016, 2017; Plawecki et al, 2013; Sloan et al, 2018; Suchankova et al, 2017).…”

Section: Issues To Consider In Choosing Route Of Administrationmentioning

confidence: 99%

To Infuse or Ingest in Human Laboratory Alcohol Research

Cyders

Plawecki

Corbin

et al. 2020

Alcoholism Clin & Exp Res

Self Cite

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Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper was to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, "To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs." We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants' brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes.

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Sex Differences in Motivation to Self‐Administer Alcohol After 2 Weeks of Abstinence in Young‐Adult Heavy Drinkers

Abstract: We believe a more comprehensive study of mechanisms underlying the sex differences in the human postabstinence response is warranted.

Cited by 18 publications

References 84 publications

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

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

Sex Differences in the Neurobiology of Alcohol Use Disorder

To Infuse or Ingest in Human Laboratory Alcohol Research

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