scholarly journals Leptin Gene and Leptin Receptor Gene Polymorphisms in Alcohol Use Disorder: Findings Related to Psychopathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Brittney D. Browning ◽  
Melanie L. Schwandt ◽  
Mehdi Farokhnia ◽  
Sara L. Deschaine ◽  
Colin A. Hodgkinson ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Haplotype Diversity ◽  
Anxiety And Depression ◽  
American Group ◽  
Cigarette Pack ◽  
Leptin System

Comorbidity between alcohol use disorder (AUD) and other addictive and psychiatric disorders is highly prevalent and disabling; however, the underlying biological correlates are not fully understood. Leptin is a peptide hormone known for its role in energy homeostasis and food intake. Furthermore, leptin plays a key role in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of several neurotransmitter systems that regulate emotionality and behavior. However, human studies that have investigated circulating leptin levels in relation to AUD and affective disorders, such as anxiety and depression, are conflicting. Genetic-based analyses of the leptin gene (LEP) and leptin receptor gene (LEPR) have the potential of providing more insight into the potential role of the leptin system in AUD and comorbid psychopathology. The aim of the current study was to investigate whether genotypic variations at LEP and LEPR are associated with measures of alcohol use, nicotine use, anxiety, and depression, all of which represent common comorbidities with AUD. Haplotype association analyses were performed, using data from participants enrolled in screening and natural history protocols at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Analyses were performed separately in European Americans and African Americans due to the variation in haplotype diversity for most genes between these groups. In the European American group, one LEP haplotype (EB2H4) was associated with lower odds of having a current AUD diagnosis, two LEPR haplotypes (EB7H3, EB8H3) were associated with lower cigarette pack years and two LEPR haplotypes (EB7H2, EB8H2) were associated with higher State-Trait Anxiety Inventory (STAI-T) scores. In the African American group, one LEP haplotype (AB2H8) was associated with higher cigarette pack years and one LEP haplotype (AB3H2) was associated with lower Fagerström Test for Nicotine Dependence (FTND) scores. Overall, this study found that variations in the leptin and leptin receptor genes are associated with measures of alcohol use, nicotine use, and anxiety. While this preliminary study adds support for a role of the leptin system in AUD and psychopathologies, additional studies are required to fully understand the underlying mechanisms and potential therapeutic implications of these findings.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

Alcohol Use Disorder

2018 ◽  
Author(s):  
Igor Ponomarev
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Critical Discussion ◽  
Epigenetic Mechanisms ◽  
Future Directions ◽  
Clinically Significant ◽  
Early Life Exposures ◽  
The Brain ◽  
Epigenetic Research

Alcohol use disorder (AUD) is characterized by clinically significant impairments in health and social function. Epigenetic mechanisms of gene regulation may provide an attractive explanation for how early life exposures to alcohol contribute to the development of AUD and exert lifelong effects on the brain. This chapter provides a critical discussion of the role of epigenetic mechanisms in AUD etiology and the potential of epigenetic research to improve diagnosis, evaluate risks for alcohol-induced pathologies, and promote development of novel therapies for the prevention and treatment of AUD. Challenges of the current epigenetic approaches and future directions are also discussed.

A Developmental Perspective on the Genetic Basis of Alcohol Use Disorder

2018 ◽  
Author(s):  
Elisa M. Trucco ◽  
Gabriel L. Schlomer ◽  
Brian M. Hicks
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Developmental Perspective ◽  
Relative Contribution ◽  
Intermediate Phenotypes ◽  
Problematic Alcohol ◽  
Age Related ◽  
Genetic And Environmental Factors ◽  
Problematic Alcohol Use

Approximately 48–66% of the variation in alcohol use disorders is heritable. This chapter provides an overview of the genetic influences that contribute to alcohol use disorder within a developmental perspective. Namely, risk for problematic alcohol use is framed as a function of age-related changes in the relative contribution of genetic and environmental factors and an end state of developmental processes. This chapter discusses the role of development in the association between genes and the environment on risk for alcohol use disorder. Designs used to identify genetic factors relevant to problematic alcohol use are discussed. Studies examining developmental pathways to alcohol use disorder with a focus on endophenotypes and intermediate phenotypes are reviewed. Finally, areas for further investigation are offered.

scholarly journals The role of pubertal timing in the link between family history of alcohol use disorder and late adolescent substance use

2020 ◽  
Vol 210 ◽  
pp. 107955
Author(s):  
Alexander S. Weigard ◽  
Jillian E. Hardee ◽  
Robert A. Zucker ◽  
Mary M. Heitzeg ◽  
Adriene M. Beltz
Keyword(s):  
Substance Use ◽  
Family History ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Pubertal Timing ◽  
Adolescent Substance Use ◽  
Late Adolescent ◽  
Adolescent Substance ◽  
History Of

Emotional difficulties among individuals with alcohol use disorder: the mediating role of psychological mechanisms linked to mindfulness

2020 ◽  
Vol 25 (5) ◽  
pp. 561-568
Author(s):  
Marco Cavicchioli ◽  
Pietro Ramella ◽  
Giulia Simone ◽  
Giulia Vassena ◽  
Mariagrazia Movalli ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Emotional Difficulties ◽  
Mediating Role ◽  
Psychological Mechanisms

scholarly journals Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder

2020 ◽  
Author(s):  
Eleonora Gatta ◽  
Alessandro Guidotti ◽  
Vikram Saudagar ◽  
Dennis R Grayson ◽  
Dario Aspesi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Promoter Region ◽  
Alcohol Use Disorder ◽  
Hydroxysteroid Dehydrogenase ◽  
Fine Tuning ◽  
Translocator Protein ◽  
Gas Chromatography Mass Spectrometry ◽  
Gabaergic Neurotransmission

Abstract Background Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. Methods In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. Results The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. Conclusion Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

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