Fine-tuning Muscarinic Cholinergic Transmission in Alcohol Use Disorder

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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DSM-5 alcohol use disorder features among treatment-seeking older adults

SUCHT - Zeitschrift für Wissenschaft und Praxis / Journal of Addiction Research and Practice ◽

10.1024/0939-5911/a000550 ◽

2018 ◽

Vol 64 (4) ◽

pp. 185-196 ◽

Cited By ~ 2

Author(s):

Silke Behrendt ◽

Barbara Braun ◽

Randi Bilberg ◽

Gerhard Bühringer ◽

Michael Bogenschutz ◽

...

Keyword(s):

Older Adults ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

The Elderly ◽

Treatment Seeking ◽

Controlled Clinical Trial ◽

Dsm 5 ◽

Wide Range ◽

And Gender ◽

International Multicenter

Abstract. Background: The number of older adults with alcohol use disorder (AUD) is expected to rise. Adapted treatments for this group are lacking and information on AUD features in treatment seeking older adults is scarce. The international multicenter randomized-controlled clinical trial “ELDERLY-Study” with few exclusion criteria was conducted to investigate two outpatient AUD-treatments for adults aged 60+ with DSM-5 AUD. Aims: To add to 1) basic methodological information on the ELDERLY-Study by providing information on AUD features in ELDERLY-participants taking into account country and gender, and 2) knowledge on AUD features in older adults seeking outpatient treatment. Methods: baseline data from the German and Danish ELDERLY-sites (n=544) were used. AUD diagnoses were obtained with the Mini International Neuropsychiatric Interview, alcohol use information with Form 90. Results: Lost control, desired control, mental/physical problem, and craving were the most prevalent (> 70 %) AUD-symptoms. 54.9 % reported severe DSM-5 AUD (moderate: 28.2 %, mild: 16.9 %). Mean daily alcohol use was 6.3 drinks at 12 grams ethanol each. 93.9 % reported binging. More intense alcohol use was associated with greater AUD-severity and male gender. Country effects showed for alcohol use and AUD-severity. Conclusion: European ELDERLY-participants presented typical dependence symptoms, a wide range of severity, and intense alcohol use. This may underline the clinical significance of AUD in treatment-seeking seniors.

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Persönliche vs. computerbasierte Alkoholintervention für Krankenhauspatienten: Studiendesign

SUCHT - Zeitschrift für Wissenschaft und Praxis / Journal of Addiction Research and Practice ◽

10.1024/0939-5911.a000394 ◽

2015 ◽

Vol 61 (6) ◽

pp. 347-355 ◽

Cited By ~ 2

Author(s):

Jennis Freyer-Adam ◽

Sophie Baumann ◽

Inga Schnuerer ◽

Katja Haberecht ◽

Ulrich John ◽

...

Keyword(s):

Public Health ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Identification Test ◽

Disorder Identification

Zusammenfassung. Ziel: Persönliche Beratungen können bei stationären Krankenhauspatienten Alkoholkonsum und Mortalität reduzieren. Sie sind jedoch mit hohen Kosten verbunden, wenn aus Public-Health-Erfordernis viele Menschen einer Bevölkerung erreicht werden müssen. Computerbasierte Interventionen stellen eine Alternative dar. Jedoch ist ihre Wirksamkeit im Vergleich zu persönlichen Beratungen und im Allgemeinkrankenhaus noch unklar. Eine quasi-randomisierte Kontrollgruppenstudie „Die Bedeutung der Vermittlungsform für Alkoholinterventionen bei Allgemeinkrankenhauspatienten: Persönlich vs. Computerisiert“ soll dies untersuchen. Design und Methoden werden beschrieben. Methode: Über 18 Monate sind alle 18- bis 64-jährigen Patienten auf Stationen der Universitätsmedizin Greifswald mittels Alcohol Use Disorder Identification Test (AUDIT) zu screenen. Frauen/Männer mit AUDIT-Consumption ≥ 4/5 und AUDIT < 20 werden einer von drei Gruppen zugeordnet: persönliche Intervention (Beratungen zur Konsumreduktion), computerbasierte Intervention (individualisierte Rückmeldebriefe und Broschüren) und Kontrollgruppe. Beide Interventionen erfolgen im Krankenhaus sowie telefonisch bzw. postalisch nach 1 und 3 Monaten. In computergestützten Telefoninterviews nach 6, 12, 18 und 24 Monaten wird Alkoholkonsum erfragt. Schlussfolgerung: Das Studienvorhaben, sofern erfolgreich umgesetzt, ist geeignet die längerfristige Wirksamkeit einer persönlichen und computerbasierten Intervention im Vergleich zu untersuchen.

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