Name: George Breese
Hometown: Richmond, Ind. Education: B.S. in Pharmacy, Butler University, 1959; M.S. in Pharmacology, Butler University, 1961; Ph.D. in Pharmacology, University of Tennessee, 1965. Experience: Instructor of Pharmacology, University of Arkansas Medical School, 1965-66; Research Associate, National Institute of General Medical Sciences and National Institutes of Mental Health, 1966-68; Professor, Psychiatry and Pharmacology, University of North Carolina at Chapel Hill, 1968-present; Research Scientist, Brain & Development Research Center, UNC-CH, 1970-present; Research Scientist, Center for Alcohol Studies, UNC-CH, 1977-present; Research Professor, Anesthesiology, UNC-CH, 1995-present. Honors and Awards: Rho Chi Honor Society, 1958; Phi Kappa Phi Honor Society, 1959; U.S. Public Health Service Predoctoral Training Fellowship, 1964-65; U.S. Public Health Service Career Development Awards, 1970-75 and 1975-1980. Family: Married Joan C. Skates in 1960. Two children and one granddaughter.
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When George Breese came to the University of North Carolina at Chapel Hill in 1968, he was interested in studying mental disease, not alcoholism.
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Ethanol: a simple molecule with a surprising amount of specificity.
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But, in pursuing this avenue of research, he got hooked on studying the effects of alcohol on the brain. It was a simple experiment, and a bit of luck, that grabbed the attention of this young researcher.
Breese, along with researchers Morris Lipton and Arthur Prange, was investigating the ability of thyrotropin-releasing hormone (TRH) to reverse the effects of drugs, such as Nembutal, that act as sedatives. At the time this research was being done, in the early 1970s, the only defined function of TRH was to act on the pituitary – a small gland located at the base of the brain – triggering it to release two hormones.
After demonstrating that TRH did have extrapituitary effects – namely antagonizing the action of several sedatives – Breese and his colleagues decided to test the ability of TRH to reverse the action of a different type of drug – alcohol.
Animals in a deep, ethanol-induced slumber were given a systemic injection, an injection directly into the blood stream, of TRH.
And the results – getting mice, rats and primates up off their backs and running within a short period of time – amaze Breese to this day. "I know of no other drug that will do that," he says with an incredulous look on his face. "TRH reversal of central nervous system sedation, in my opinion, is probably one of the most remarkable observations in biology that I've ever seen."
While the development of TRH into a drug that could antagonize some of the adverse properties of alcohol in humans never came to fruition, the action of TRH did raise Breese's curiosity. And recent studies have found that alcoholics and their relatives have innate differences in their responses to alcohol that might be related to differences in TRH.
During the past 24 years, Breese has focused his efforts on learning more about the action of alcohol on the brain. He has been quite successful – raising nearly $9 million in federal grants and publishing over 300 scientific articles in peer-reviewed journals. Along with these academic measures of success, Breese's work has helped to change researchers' perspective on the mechanism of alcohol's action.
Because alcohol is a simple molecule, composed only of three simple building blocks – six hydrogens, two carbons and one oxygen, its action was originally thought to be nonspecific. Researchers proposed that alcohol acted on neurons by disrupting their cell membrane, a physical barrier between the inside and outside of the cell or neuron. By dissolving in the lipids or fatty substances that make up the cell membrane, alcohol could break bonds between the lipid molecules, causing the membrane to loose some rigidity and become more fluid.
Since proteins that regulate communication between neurons are embedded within this membrane, their functions would be disrupted. Thus, this nonspecific action of alcohol on the cell membrane of neurons was hypothesized to cause alcohol-induced effects in humans.
While this non-specific action has been proposed for decades, we now know that nearly fatal alcohol concentrations are required to disrupt the cell membrane.
 Lab Associates: left to right, Darin Knapp, Edna Titus, Hugh Criswell, Gary Duncan, George Breese, Sheryl Moy, Thomas McCown, Doris Lee; Not pictured: Xiaohong Yang, En-Qi Ballard. |
Breese, with the help of a number of researchers who have worked in his laboratory, demonstrated that alcohol acts specifically in regions of the brain that express gamma amino-butyric acid (GABA) receptors, the major inhibitory neurotransmitter in brain.
The main GABA receptor, GABAA, is composed of different subunits and has a distinct distribution in brain. Numerous experiments suggest that alcohol consumption, by enhancing the inhibitory action of GABA at specific GABAA receptor subtypes, leads to a loss of coordination, reduces anxiety and contributes to drug dependence. Tranquilizers, such as Valium and other benzodiazepines, also act by potentiating GABAA receptors.
Breese’s laboratory is currently determining what GABAA receptor subtypes are present in the brain regions that are sensitive to ethanol. The type I benzodiazepine-GABAA receptor appears to be the primary site of ethanol’s actions at concentrations of ethanol around the legal driving limit. “Our ultimate goal is to define the proteins that make up the alcohol sensitive receptor,” he says. Breese hopes that this knowledge will help to elucidate why alcohol’s action is specific.
Benzodiazepine-GABA receptorsare made up of a combination of 13 possible protein subunits. Preliminary results from Breese's lab suggest that alcohol acts on a specific receptor composed of three such subunits. But the investigation doesn't stop there. "The question is," Breese ponders, "why does it choose that one over some of the others?"
The specificity of alcohol is not limited to GABA receptors. Breese’s laboratory has found a similar specificity exists for N-methyl-D-aspartate (NMDA), nicotinic cholinergic and glycine receptors in neurons, and proposes that this specificity probably exists for other neuronal receptors that have not yet been studied.
The differential distribution of receptor subtypes in brain results in alcohol specifically affecting different parts of the brain. The unique responses alcoholics have to alcohol might be related to different types and/or different brain distribution of receptor subtypes. Although many receptors occur throughout the brain, Breese’s work has helped to elucidate which brain regions might be affected and why alcohol selectively affects specific regions.
Today, alcohol researchers accept these findings and have reproduced some of the experiments demonstrating the specificity of alcohol's action, confirming the work of Breese's lab.
But Breese, with a smile, recalls that the research proposals outlining this work in his initial grant applications were probably considered "crazy" at the time.
"Ethanol is a very unusual drug," he says. "It's incredibly unexpected that you would have any specificity for alcohol."
Breese's research has also included investigating the underlying molecular basis of alcohol-induced depression, withdrawal and susceptibility to seizures.
He attributes the success of his laboratory to its multidisciplinary approach – using tools and techniques developed in different fields, including psychiatry, pharmacology, physiology and anatomy. "That way you can work all the way from the test tube to the animal," he says. "So you can really define what may be relevant to alcohol and its effects."
Although Breese is a self-proclaimed "health-nut" who has never made drinking part of his being, he recognizes the far-reaching clinical implications of alcohol, a drug whose use is related to about 25 percent of all physical ailments. "We work on alcohol because it's an important medical problem," he says.
Growing up in a small town of about 500 people in Indiana, Breese
has also witnessed the social problems caused by alcoholism. "Working
in a drug store and also as a pharmacist in a small farming community,
you get a better feel for what a devastating effect alcohol has
on a family," he says.
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| Updated November 22, 1996 | Comments to web developer |
