Journal
MOLECULAR PSYCHIATRY
Volume 23, Issue 5, Pages 1303-1319Publisher
SPRINGERNATURE
DOI: 10.1038/mp.2017.63
Keywords
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Funding
- European Union [LSHM-CT-2007-037286]
- FP7 project IMAGEMEND [602450]
- FP7 project AGGRESSOTYPE [602805]
- FP7 project MATRICS [603016]
- Innovative Medicine Initiative Project EU-AIMS [115300-2]
- Medical Research Council [93558]
- Consortium on Vulnerability to Externalizing Disorders and Addictions [c-VEDA] [MR/N000390/1]
- VR
- FORTE
- FORMAS
- Wellcome Trust (Behavioural and Clinical Neuroscience Institute, University of Cambridge)
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- King's College London
- Bundesministerium fur Bildung und Forschung (BMBF) [01GS08152, 01EV0711, eMED SysAlc01ZX1311A, 01GQ113]
- Deutsche Forschungsgemeinschaft (DFG) [SM 80/7-1, SM 80/7-2, SFB 940/1]
- ANR [AF12-NEUR000801 - WM2NA, ANR-12-SAMA-0004]
- Fondation de France
- Fondation pour la Recherche Medicale
- Mission Interministerielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA)
- Assistance-Publique-Hopitaux-de-Paris
- INSERM
- Paris Sud University IDEX
- National Institutes of Health, U.S.A. [RO1 MH085772-01A1]
- NIH Consortium [U54 EB020403]
- cross-NIH alliance
- German Center for Cardiovascular Research
- MRC [MR/N000390/1, G0901858] Funding Source: UKRI
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In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with beta-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.
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