A new study has been released detailing the metabolic signaling pathway which affects excessive alcohol consumption. The researchers used mice as a model and analyzed data on human variations of the Nf1 gene from about 9,000 people. Nf1 is viewed as a substance abuse rare risk gene. Mice with functional Nf1 genes steadily increased their ethanol intake starting after just one episode of withdrawal. On the other hand mice with a partially deleted Nf1 gene showed no increase in alcohol consumption. In mice with partially deleted Nf1 genes, alcohol consumption did not further increase GABA release in the central amygdala. In contrast, in mice with functional Nf1 genes, alcohol consumption resulted in an increase in central amygdala GABA.
The TSRI research team suspected that Nf1 might be relevant to alcohol-related GABA activity in an area of the brain called the central amygdala, which is important in decision-making and stress- and addiction-related processes.
The TSRI gene called neurofibromatosis type 1 (Nf1) regulates gamma-aminobutyric acid (GABA), a neurotransmitter that lowers anxiety and increases feelings of relaxation. Variations in the human version of the NF1 gene are linked to aclohol dependence risk and severity in patients.
“This novel and seminal study provides insights into the cellular mechanisms of alcohol dependence,” said TSRI Associate Professor Marisa Roberto, a co-author of the paper. “Importantly, the study also offers a correlation between rodent and human data.”
“Despite a significant genetic contribution to alcohol dependence, few risk genes have been identified to date, and their mechanisms of action are generally poorly understood,” said TSRI Staff Scientist Vez Repunte-Canonigo, co-first author of the paper with TSRI Research Associate Melissa Herman.
“As GABA release in the central amygdala has been shown to be critical in the transition from recreational drinking to alcohol dependence, we thought that Nf1 regulation of GABA release might be relevant to alcohol consumption,” said Herman.
The human gene analysis of 9000 people showed showed an association between the gene and alcohol-dependence risk and severity.
Vez Repunte-Canonigo, Melissa Herman, Tomoya Kawamura, Henry R. Kranzler, Richard Sherva, Joel Gelernter, Lindsay A. Farrer, Marisa Roberto, Pietro Paolo Sanna. Nf1 regulates alcohol dependence-associated excessive drinking and GABA release in the central amygdala in mice, and is associated with alcohol dependence in humans.. Biological Psychiatry, 2014; DOI: 10.1016/j.biopsych.2014.07.031