Sex moderates stress reactivity in heavy drinkers

Hartwell, Emily E.; Ray, Lara A.

doi:10.1016/j.addbeh.2013.06.016

Cited by 36 publications

(24 citation statements)

References 27 publications

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“…Of relevance to the dopaminergic hypothesis of addiction, the interaction between attachment and dopaminergic genotype has been investigated in relation to alcohol use problems in young adults, but no association has been found [ 68 ]. Moreover, females should also be studied, since sex differences in stress reactivity and addiction are rather the rule than the exception [ 69 , 70 ]; FKBP5 genotype was for instance found to mediate the cortisol stress response in male but not female young adults [ 71 ]. The findings on humans have to be understood with respect to these boundaries (see also Strengths and Limitations ) and call for independent replications.…”

Section: Fkbp5 Genotype In Relation To Parent-child Relationmentioning

confidence: 99%

Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans

et al. 2016

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Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0157-z) contains supplementary material, which is available to authorized users.

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Section: Fkbp5 Genotype In Relation To Parent-child Relationmentioning

confidence: 99%

Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans

et al. 2016

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“…There are a wide variety of potential explanations for sex differences in AUD vulnerability. For example, sexual dimorphisms in stress reactivity and stress-related disorders ( Breslau et al, 1998 ; Bangasser et al, 2010 ; Hartwell and Ray, 2013 ; Bangasser and Valentino, 2014 ; Bandelow and Michaelis, 2015 ) could be partly responsible ( Lynch, 2006 ). A preponderance of evidence indicates that stress-related psychiatric disorders, such as anxiety and post-traumatic stress disorder, occur more frequently in women than men ( Breslau et al, 1998 ; Bangasser et al, 2010 ; Hartwell and Ray, 2013 ; Bangasser and Valentino, 2014 ; Bandelow and Michaelis, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Sex and β-Endorphin Influence the Effects of Ethanol on Limbic Gabra2 Expression in a Mouse Binge Drinking Model

et al. 2018

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Binge drinking is a widespread problem linked to increased risk for alcohol-related complications, including development of alcohol use disorders. In the last decade, binge drinking has increased significantly, specifically in women. Clinically, sexually dimorphic effects of alcohol are well-characterized, however, the underlying mechanisms for these dimorphisms in the physiological and behavioral effects of alcohol are poorly understood. Among its many effects, alcohol consumption reduces anxiety via the inhibitory neurotransmitter GABA, most likely acting upon receptors containing the α-2 subunit (Gabra2). Previous research from our laboratory indicates that female mice lacking the endogenous opioid peptide β-endorphin (βE) have an overactive stress axis and enhanced anxiety-like phenotype, coupled with increased binge-like alcohol consumption. Because βE works via GABA signaling to reduce anxiety, we sought to determine whether sexually dimorphic binge drinking behavior in βE deficient mice is coupled with differences in CNS Gabra2 expression. To test this hypothesis, we used βE knock-out mice in a “drinking in the dark” model where adult male and female C57BL/6J controls (βE +/+) and βE deficient (βE -/-; B6.129S2-Pomctm1Low/J) mice were provided with one bottle of 20% ethanol (EtOH) and one of water (EtOH drinkers) or two bottles of water (water drinkers) 3 h into the dark cycle for four consecutive days. Following a binge test on day 4, limbic tissue was collected and frozen for subsequent qRT-PCR analysis of Gabra2 mRNA expression. Water-drinking βE +/+ females expressed more Gabra2 in central nucleus of the amygdala and the bed nucleus of the stria terminalis than males, but this sex difference was absent in the βE -/- mice. Genotype alone had no effect on alcohol consumption or drug-induced increase in Gabra2 expression. In contrast, βE expression had bi-directional effects in females: in wildtypes, Gabra2 mRNA was reduced by binge EtOH consumption, while EtOH increased expression in βE -/- females to levels commensurate with drug-naïve βE +/+ females. These results support the contention that βE plays a role in sexually dimorphic binge-like EtOH consumption, perhaps through differential expression of GABAA α2 subunits in limbic structures known to play key roles in the regulation of stress and anxiety.

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“…Stress is a primary trigger of alcohol craving and relapse (Seo and Sinha, 2014), and females display stronger relationships between stress, craving in heavy drinkers and relapse in former drinkers than males (Hartwell and Ray, 2013; Heffner et al, 2011). Females are more likely to develop anxiety-related disorders (McLean et al, 2011) and show a stronger relationship between lifetime trauma and alcohol relapse propensity (Heffner et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction

2017

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Alcohol use disorders are chronically relapsing conditions that pose significant health challenges for our society. Stress is a prevalent trigger of relapse, particularly for women, yet the mechanisms by which alcohol and stress interact, and how this differs between males and females, remain poorly understood. The glutamatergic circuit connecting the basolateral (BLA) and central (CeA) nuclei of the amygdala is a likely locus for such adaptations, yet the impact of alcohol, corticosterone and their interaction on this circuit has been understudied. In particular, no studies have addressed sex differences in these effects or potential differential responses between the lateral and medial subdivisions of the central nucleus. Thus, we assessed the effects of alcohol and corticosterone treatments on BLA-evoked compound glutamatergic responses in medial and lateral CeA neurons from male and female rats. We observed minimal differences between medial and lateral CeA responses to alcohol and corticosterone in male rats, which were primarily sensitive to alcohol-induced inhibition of glutamatergic postsynaptic potentials. Unlike male neurons, cells from female rats displayed reduced sensitivity to alcohol’s inhibitory effects. In addition, female neurons diverged in their sensitivity to corticosterone, with lateral CeA neuronal responses significantly blunted following corticosterone treatment and medial CeA neurons largely unchanged by corticosterone or subsequent co-application of alchol. Together these data highlight striking differences in how male and female amygdala respond to alcohol and the stress hormone corticosterone, factors which may impact differential susceptibility of the sexes to alcohol- and stress-related disorders.

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Sex moderates stress reactivity in heavy drinkers

Cited by 36 publications

References 27 publications

Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans

Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans

Sex and β-Endorphin Influence the Effects of Ethanol on Limbic Gabra2 Expression in a Mouse Binge Drinking Model

Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction

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