Professor, Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical CampusView Slides
Alcohol is an “addictive” drug, but its use is condoned by government, and it is used by many individuals who enjoy social drinking and never become dependent on it. However, about 7 percent of alcohol drinkers 18 years of age and older in the U.S. develop what is now called Alcohol Use Disorder (AUD). In addition, many men and women drink alcohol at “hazardous” levels, which can lead to organ damage and is responsible for more than 3 million deaths per year worldwide. AUD is psychiatrically defined by the presence of 11 signs, and the number of signs during a 12-month period defines the severity of AUD. These signs include the narrowing of repertoire to focus on obtaining, using, or recovering from alcohol effects; unsuccessful efforts to reduce alcohol use; alcohol use resulting in failure to fulfill major role objectives; continued use despite adverse consequences and craving (a strong desire or urge to use alcohol) (DSM-V criteria). Many of these criteria also apply to other addictive drugs, and alcohol can produce many of the same neurobiological effects as the other addictive drugs. But, alcohol also has unique characteristics and mechanisms of action in the central nervous system.
The effects of alcohol in the brain derive from alcohol’s ability to interfere with the activity of the two major neurotransmitters, GABA (the major inhibitory neurotransmitter) and glutamate (the major excitatory neurotransmitter), and the interaction of these transmitters with other modulating systems that contribute to the rewarding effects of alcohol. Maladaptations of these systems occur with chronic alcohol use and lead to the signs and symptoms of AUD. However, not everyone who uses alcohol, even at hazardous levels, develops AUD.
Numerous studies have estimated that the genetic constitution of an individual can contribute up to 50 percent of the likelihood of the development of AUD, and human genetic analyses have suggested particular subsets of genes that may underlie this vulnerability. A conceptual transition has occurred over the last 10 years, in that rather than looking for a gene responsible for complex phenotypes such as AUD, it has become common to consider that interacting genetic elements (i.e., networks of gene products) are responsible for the complex phenotype.
Our current work uses a systems genetic approach to understand the transcriptional and signaling networks in the brain that influence alcohol drinking, a prerequisite for development of AUD. The characterization of this genetically controlled “brain connectome” promises to provide the basis for developing rational pharmacological approaches to reducing alcohol consumption and the craving for alcohol in individuals suffering from AUD.
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