A new research study by the Scripps Research Institute, published in the journal Proceedings of the National Academy of Science, has revealed the metabolic pathway of a brain protein is involved in regulating binge drinking. Deleting the gene that is responsible for gene expression increased alcohol consumption and prevented the brain from signaling the rewarding properties of alcohol.
“Alcohol hits a lot of different targets in our brain, which makes disentangling the in vivo effects of alcohol quite complicated,” said TSRI biologist Candice Contet, senior author of the study. “Our study sheds light on the molecular mechanisms implicated in binge drinking.”
The CDC considers binge drinking to be a public health risk as it increases risky behavior and has an adverse impact on health contributing to cardiovascular disease, liver disease and neurological damage. The study is the first of its kind to identify the metabolic pathway including the role of a member of the “G protein-gated inwardly rectifying potassium channel” (GIRK) family in the behavioral and cellular responses to alcohol.
GIRK channels impact by decreasing the ability of neurons to send signals. Alcohol acts by activating GIRK channels; however, the researchers were not aware of the impact of this metabolic pathway on neurons. The GIRK3 subunit has previously been shown to modulate the effects of other drugs, such as the “date rape drug” γ-hydroxybutyrate (GHB) and cocaine.
The research findings revealed that the deletion of GIRK3 caused decreased convulsions as a result of the decreased ability of neurons to fire during alcohol withdrawal. The results have a direct correlation to the reward seeking pathway involved in drug and alcohol abuse. This pathway originates in an area of the midbrain called the ventral tegmental area (VTA) and releases the neurotransmitter dopamine in two forebrain areas: the ventral striatum and the prefrontal cortex. Alcohol, like other drugs of abuse, activates this pathway.
“The dramatic effect of GIRK3 deletion on the ability of alcohol to excite VTA neurons was surprising,” said Melissa Herman, a research associate in the laboratory of TSRI Professor Marisa Roberto and first author of the study. “Even when applied at a very high concentration, alcohol was unable to alter the firing of neurons missing GIRK3.”
“The strength of this study relied on our multidisciplinary approach — the combination of molecular, cellular and behavioral analyses — to understand the implication of GIRK3 in the effects of alcohol,” said Candice Contet, the lead study author. “This was made possible by the uniquely collaborative environment of our department (the TSRI Committee on the Neurobiology of Addictive Disorders), with the laboratories of Marisa Roberto and Larry Parsons readily stepping in when expertise in electrophysiology and microdialysis was needed to address our scientific question.”
Melissa A. Herman, Harpreet Sidhu, David G. Stouffer, Max Kreifeldt, David Le, Chelsea Cates-Gatto, Michaelanne B. Munoz, Amanda J. Roberts, Loren H. Parsons, Marisa Roberto, Kevin Wickman, Paul A. Slesinger, and Candice Contet. GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. PNAS, April 2015 DOI: 10.1073/pnas.1416146112