AUSTIN, Texas—New research by scientists at The University of Texas at Austin has revealed evidence of special pathways in the brain where ethanol, the alcohol found in intoxicating beverages, may have its impact. Alcoholism and addiction researchers have been searching for years for the specific areas in the central nervous system that are affected by alcohol. If they can identify such target areas, they may be able to develop molecular treatments that would interfere with the action of alcohol at these particular sites.
The researchers include faculty from UT Austin’s Waggoner Center for Alcohol and Addiction Research and Section on Neurobiology and the department of pharmacology and toxicology in the College of Pharmacy. They believe they have at last isolated promising alcohol targets in special brain pathways referred to as GIRKs, or G-Protein-coupled Inwardly Rectifying Potassium Channels.
“The cellular effects of alcohol and the central nervous system have significant implications for understanding alcohol addiction,” said Dr. R. Adron Harris, director of the Waggoner Center and a co-author of the research. Harris said that GIRKs are widely distributed throughout the brain and are involved in regulating inhibitory responses in the central nervous system. “We are working to determine how GIRKs influence alcohol consumption and dependence,” he said.
“Molecular analysis of this cell membrane channel ultimately will increase our knowledge of how alcohol affects the brain and, thereby, the way a person functions,” said Dr. Enoch Gordis, director of the National Institute on Alcohol Abuse and Alcoholism.
The Waggoner Center is supported by grants from NIAAA, a branch of the National Institutes of Health, as well as the Texas Commission on Alcohol and Drug Abuse.
While alcoholism is a major disease, Harris said there are not that many weapons available in the medical arsenal to combat it. In the case of depression, in contrast, there are multiple drugs on the market as well as different behavioral or talking therapies that can be used.
“If you think about depression, there are all different kinds of modalities of treatment,” Harris said. “For alcoholism, there is very little variety and the relapse rate is very high after all existing treatments.”
Before developing effective treatments, researchers must learn more about the physical mechanisms in the brain that are involved in intoxication, addiction and cravings for alcohol.
Harris explained that the central nervous system is equivalent to the electrical wiring in a house, with the brain as the main center for messages transmitted by the wiring throughout the body. The wiring comes complete with a series of switches that can promote or inhibit the transmission of messages. One goal of the research is to discover ways the “switches” work.
The wiring, which consists of neurons, isn’t really solid, Harris said, continuing the metaphor. It’s more like a series of tiny pipelines with little adjustable openings, or channels composed of proteins. The channels expand or contract in response to the action of the switches.
Opiate drugs such as morphine and codeine act on some of the switches in a way that causes them to inhibit the transmission of pain messages through the spinal cord. The opiates bind to receptors in the brain activating GIRK channels that, in turn, inhibit electrical transmission. A substance such as caffeine produces the opposite effect. Caffeine interferes with GIRK channels in a way that causes people to become wide-awake.
“We know these GIRK channels play an important part in the behavioral effects of drugs because of the actions of caffeine and morphine,” Harris said. “But the exact consequences of alcohol activation of GIRK channels isn’t known, and that is the next step.
“The question is how does alcohol produce the effects, such as removal of inhibition or judgment, lack of coordination. The behavior (of an intoxicated person) is well known. The question is what mechanism causes this,” Harris said. “The long range goal is to develop medication that will interfere at the sites of alcohol action, and prevent the craving and excessive consumption of alcohol abusers.”
Potassium channels such as GIRKs specifically regulate neuron-to-neuron communication as well as the rate at which communication takes place. But not all potassium channels are sensitive to ethanol. In fact, the researchers tested 20 different potassium channels, most of which are resistant. The fact that some GIRKs are highly sensitive to levels of alcohol that produce mild intoxication may mean that GIRKs have a substantial impact on the capacity of neurons to communicate.
Work of the UT Austin researchers was reported in the December issue of Nature Neuroscience (Vol. 2, No. 12). Lead author of the paper was Dr. Joanne Lewohl, a research fellow at the Waggoner Center, with Dr. Richard A. Morrisett, associate professor in the College of Pharmacy, as a co-author. Harris, senior author of the paper, said similar research has been going on in Japan and that his Japanese counterparts report similar findings on GIRKs in the same issue of the journal.
For more information, contact Dr. R. Adron Harris, director of the Waggoner Center, (512) 232-2514.
