ArticleProceedings of the National Academy of Sciences of the United States of America2012
RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 2 of them syntheses that pooled it.
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Who cites it
52 citing papers in PubMed, 2 syntheses or guidelines pooled it, 95 citations in OpenAlex.
- The IMAGEN study: a decade of imaging genetics in adolescents.Molecular psychiatry · 2020Pooled it
- New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.Nature human behaviour · 2019Pooled it
- A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men.PloS one · 2016Trial
- Discovery of gene-alcohol interaction loci influencing blood pressure in 1.1 million individuals from multiple populations.Research square · 2026Article
- Reward Deficiency Syndrome (RDS): A Common Neurogenetic Trait/State of All Addictions: Is this the new DSM?British journal of healthcare and medical research · 2026Article
- Externalizing as a common genetic influence for a broad spectrum of substance use and behavioral conditions: A developmental perspective from the Avon Longitudinal Study of Parents and Children.Addiction (Abingdon, England) · 2025Article
- GBA1 Gene-Associated Transcriptomic Signatures Reveal Risk Genes in Parkinson's Disease.Biomedicines · 2025Article
- DNAJC13 influences responses of the extended reward system to conditioned stimuli: a genome-wide association study.European archives of psychiatry and clinical neuroscience · 2025Article
- RASGRF2 as a potential pathogenic gene mediating the progression of alcoholic hepatitis to alcohol-related cirrhosis and hepatocellular carcinoma.Discover oncology · 2025Article
- Behavioral Neurobiology of Alcohol Addiction: A Decade of Great Challenges, New Hopes, and Hypes.Current topics in behavioral neurosciences · 2025Review
- Where Top-Down Meets Bottom-Up: Cell-Type Specific Connectivity Map of the Whisker System.Neuroinformatics · 2024Article
- Optical Genome Mapping Reveals Disruption of theGenes · 2024Article
- The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.Molecular psychiatry · 2023Article
- Researching Mitigation of Alcohol Binge Drinking in Polydrug Abuse: KCNK13 and RASGRF2 Gene(s) Risk Polymorphisms Coupled with Genetic Addiction Risk Severity (GARS) Guiding Precision Pro-Dopamine Regulation.Journal of personalized medicine · 2022Article
- Ten Points to Improve Reproducibility and Translation of Animal Research.Frontiers in behavioral neuroscience · 2022Article
- Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice.Frontiers in pharmacology · 2022Article
- Reward Deficiency Syndrome (RDS): A Cytoarchitectural Common Neurobiological Trait of All Addictions.International journal of environmental research and public health · 2021Article
- The Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA): an accelerated longitudinal cohort of children and adolescents in India.Molecular psychiatry · 2020Review
- Identifying biological markers for improved precision medicine in psychiatry.Molecular psychiatry · 2020Review
- Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease.Frontiers in neurology · 2020Article
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Authors and funding
45 authors at 20 institutions in 9 countries.
Funding
Abstract
The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.