Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals
Open accessAbstract
Understanding risk factors for substance use disorders (SUD) can facilitate medication development for SUD treatment. While a rich literature exists discussing environmental factors that influence SUD, fewer articles have focused on genetic factors that convey vulnerability to drug use. Methods to identify SUD risk genes include Genome-Wide Association Studies (GWAS) and transgenic approaches. GWAS have identified hundreds of gene variants or single nucleotide polymorphisms (SNPs). However, few genes identified by GWAS have been verified by clinical or preclinical studies. In contrast, significant progress has been made in transgenic approaches to identify risk genes for SUD. In this article, we review recent progress in identifying candidate genes contributing to drug use and addiction using transgenic approaches. A central hypothesis is if a particular gene variant (e.g., resulting in reduction or deletion of a protein) is associated with increases in drug self-administration or relapse to drug seeking, this gene variant may be considered a risk factor for drug use and addiction. Accordingly, we identified several candidate genes such as those that encode dopamine D 2 and D 3 receptors, mGluR 2, M 4 muscarinic acetylcholine receptors, and α 5 nicotinic acetylcholine receptors, which appear to meet the risk-gene criteria when their expression is decreased. Here, we describe the role of these receptors in drug reward and addiction, and then summarize major findings from the gene-knockout mice or rats in animal models of addiction. Lastly, we briefly discuss future research directions in identifying addiction-related risk genes and in risk gene-based medication development for the treatment of addiction.
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Gene variants can exert effects indirectly by influencing brain development, personality traits, drug metabolic pathways, neurotransmitters, neural circuitry, or cellular physiology.
“Gene variants can also exert their effects indirectly, by influ encing brain development, including the rate at which frontal connections mature; personality traits that may predispose to drug- seeking, such as sensation seeking; drug metabolic path ways that result in faster or slower degradation of drugs; neu rotransmitters that are directly or indirectly implicated in drug reward and neuroplast”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [99]
The Introduction (page unavailable) discusses genes involved in dopaminergic and other neurotransmitter systems and identifies novelty seeking as a trait associated with substance use disorders. Conclusions and Future Directions (page unavailable) also says genetic changes can affect proteins, circuits, and behavior. The copy does not establish the claimed pathways through frontal-connection maturation or faster or slower drug degradation, so it supports only part of the list. (LLM, conf=0.83)
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Volkow, N. D., & Blanco, C. (2023) · World psychiatry · doi:10.1002/wps.21073 · Cited by 503 · see citing works
Belfiore, C. I., Galofaro, V., Cotroneo, D., Lopis, A., Tringali, I., Denaro, V., & Casu, M. (2024) · Psychoactives · doi:10.3390/psychoactives3020013 · Cited by 67 · see citing works
- Authors
- Jordan, C. J., & Xi, Z.-X.
- Affiliations
- Harvard University (US)
- National Institute on Drug Abuse (US)
- Corresponding author
- Jordan, Chloe J.
- Xi, Zheng-Xiong
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-01-12
- Volume
- 15
- Pages
- 811192-811192
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC8789752
- OpenAlex
- W4205446608
- Cited by
- 20
- References
- 168
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 2
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DA000633, DA-000633-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- substance use disorders, transgenic animal models, knockout mice, dopamine D2 receptor, dopamine D3 receptor, mGluR2, self-administration, drug reward
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