The Potential Role of Glucocorticoids and the HPA Axis in Alcohol Dependence

Stephens, Mary Ann C.; McCaul, Mary E.; Wand, Gary S.

doi:10.1016/b978-0-12-405941-2.00021-3

Cited by 297 publications

(409 citation statements)

References 251 publications

(188 reference statements)

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“…A clinical diagnosis of alcohol use disorder represents a well-defined although less common outcome and does not include the more widespread hazardous alcohol use in the population that remains undetected by clinical registers. Overall, chronic life stress constitutes an established adverse determinant for alcohol dependence, possibly mediated by constitutional or stress-induced dysregulations in the hypothalamic-pituitary-adrenal axis functioning and cortisol reactivity29 contributing therefore to an increased alcohol use vulnerability. A moderate heritability for alcohol dependence is firmly established,30 but neuroendocrine stress hyper-reactivity has also been associated with a family history of alcohol dependence in healthy adult offspring 31.…”

Section: Discussionmentioning

confidence: 99%

Low stress resilience in late adolescence and risk of smoking, high alcohol consumption and drug use later in life

Kennedy

Chen

Fang

et al. 2019

J Epidemiol Community Health

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BackgroundWhile compromised stress resilience constitutes a recognised risk factor for somatic and psychiatric disease development in general, the knowledge about how individual variation in vulnerability to stress may specifically influence the long-term risks of disadvantageous health behaviours is limited.MethodsIn this Swedish cohort study, we aimed to investigate the association between stress resilience in late adolescence and adult use of addictive substances. We included 9381 men with information on psychological stress resilience measured during military conscription examinations, who later responded to an extensive health survey (mean age 34.0±7.2 years) including detailed information on substance use. We modelled continuous outcomes using linear regression, binary outcomes with logistic regression and other categorical outcomes with multinomial logistic regression.ResultsWe found that low stress resilience in adolescence conferred increased risks of all studied measures of addictive behaviour. After adjusting for childhood socioeconomic information, low stress resilience was associated with adult current regular smoking (relative risk ratio: 5.85, 95% CI 4.32 to 7.93), higher nicotine dependence scores (beta: 0.76, 95% CI 0.29 to 1.23), hazardous use of alcohol (>14 alcoholic drink-equivalents per week, OR: 1.72, 95% CI 1.37 to 2.16), DSM-IV criteria for alcohol dependence (OR: 1.74, 95% CI 1.35 to 2.25), and drug use (OR: 1.77, 95% CI 1.51 to 2.08). The results remained largely unchanged after further adjustments for adult educational attainment and occupation as well as for additional conscription covariates.ConclusionLow stress resilience in late adolescence appears to be associated with an increased risk of disadvantageous and addictive health behaviours in adulthood.

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Section: Discussionmentioning

confidence: 99%

Low stress resilience in late adolescence and risk of smoking, high alcohol consumption and drug use later in life

Kennedy

Chen

Fang

et al. 2019

J Epidemiol Community Health

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“…The mesolimbic dopamine (DA) system is implicated in the development of all addictions and is also stimulated by stress [33]. This “reward” pathway originates in the ventral tegmental area of the midbrain and projects to the nucleus accumbens, the limbic system and the orbitofrontal cortex.…”

Section: The Genetic Basis Of Vulnerability To Alcoholismmentioning

confidence: 99%

Genetic Influences on the Development of Alcoholism

Enoch

2013

Curr Psychiatry Rep

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Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive. The strongest findings are with genes encoding alcohol metabolizing enzymes. A few candidate genes such as GABRA2 have shown robust associations with alcoholism. Moreover, it has become apparent that variants in stress-related genes such as CRHR1, may only confer risk in individuals exposed to trauma, particularly in early life. Over the past decade there have been tremendous advances in large scale SNP genotyping technologies allowing for genome-wide associations studies (GWAS). As a result, it is now recognized that genetic risk for alcoholism is likely to be due to common variants in very many genes, each of small effect, although rare variants with large effects might also play a role. This has resulted in a paradigm shift away from gene centric studies towards analyses of gene interactions and gene networks within biologically relevant pathways.

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“…Alterations in HPA axis responsivity contribute to the emergence of withdrawal symptoms, which in turn influence the risk of relapse (Adinoff et al, 1998(Adinoff et al, , 2005Becker, 2012). Alcohol-dependent patients have increased cortisol levels despite blunted adrenocortical sensitivity during withdrawal (Costa et al, 1996;Adinoff et al, 1998;Esel et al, 2001) and the cortisol levels may be associated with relapse vulnerability (Stephens and Wand, 2012). Animal studies also have shown a considerable increase in both circulating and brain corticosterone levels following alcohol withdrawal (Rose et al, 2010) and elevated blood corticosterone levels could enhance alcohol withdrawal severity (Roberts et al, 1994) through GR activation (Sharrett-Field et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Huang

Schwandt

Chester

et al. 2014

Neuropsychopharmacol

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Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a cochaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.

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The Potential Role of Glucocorticoids and the HPA Axis in Alcohol Dependence

Cited by 297 publications

References 251 publications

Low stress resilience in late adolescence and risk of smoking, high alcohol consumption and drug use later in life

Low stress resilience in late adolescence and risk of smoking, high alcohol consumption and drug use later in life

Genetic Influences on the Development of Alcoholism

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

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