A factor analysis of global GABAergic gene expression in human brain identifies specificity in response to chronic alcohol and cocaine exposure
Open accessAbstract
Although expression patterns of GABAergic genes in rodent brain have largely been elucidated, no comprehensive studies have been performed in human brain. The purpose of this study was to identify global patterns of GABAergic gene expression in healthy adults, including trans and cis effects in the GABAA gene clusters, before determining the effects of chronic alcohol and cocaine exposure on gene expression in the hippocampus. RNA-Seq data from 'BrainSpan' was obtained across 16 brain regions from postmortem samples from nine adults. A factor analysis was performed on global expression of 21 GABAergic pathway genes. Factor specificity for response to chronic alcohol/cocaine exposure was subsequently determined from the analysis of RNA-Seq data from postmortem hippocampus of eight alcoholics, eight cocaine addicts and eight controls. Six gene expression factors were identified. Most genes loaded (≥0.5) onto one factor; six genes loaded onto two. The largest factor (0.30 variance) included the chromosome 5 gene cluster that encodes the most common GABAA receptor, α1β2γ2, and genes encoding the α3β3γ2 receptor. Genes within this factor were largely unresponsive to chronic alcohol/cocaine exposure. In contrast, the chromosome 4 gene cluster factor (0.14 variance) encoding the α2β1γ1 receptor was influenced by chronic alcohol/cocaine exposure. Two other factors (0.17 and 0.06 variance) showed expression changes in alcoholics/cocaine addicts; these factors included genes involved in GABA synthesis and synaptic transport. Finally there were two factors that included genes with exceptionally low (0.10 variance) and high (0.09 variance) expression in the cerebellum; the former factor was unaffected by alcohol/cocaine exposure. This study has shown that there appears to be specificity of GABAergic gene groups, defined by covariation in expression, for response to chronic alcohol/cocaine exposure. These findings might have implications for combating stress-related craving and relapse.
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Human genetics studies have noted associations between GABAAR genes and different aspects of alcoholism.
“Human genetics studies have noted associations between GABAAR genes and different aspects of alcoholism [93-98].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [97]
GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.
“The involvement of GABAAR genes in the abuse of and dependence on drugs that do not directly affect the GABAARs suggest that the GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [97]
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An emerging circuit pharmacology of GABAA receptors
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- Authors
- Enoch, M.-A., Baghal, B., Yuan, Q., & Goldman, D.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Enoch, Mary-Anne
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-05-22
- Volume
- 8
- Issue
- 5
- Pages
- e64014
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3661725
- OpenAlex
- W2089851966
- Cited by
- 28
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 3
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (AA000305-09, Z01AA000305)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- chronic ethanol exposure, cocaine exposure, alcoholism, cocaine dependence, hippocampus, GABA synthesis, postmortem brain, BrainSpan, cerebellum, relapse
- MeSH terms
- Adolescent, Adult, Ethanol, Alcoholism, Cerebellum, Cocaine, Factor Analysis, Statistical, Female, gamma-Aminobutyric Acid, Hippocampus, Humans, Male, Receptors, GABA-A, Gene Expression, Cocaine-Related Disorders, Young Adult, Alcoholics
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