From Genes to Geography: The Cutting Edge of Alcohol Research
 The development
of alcohol use problems, including alcoholism, is influenced by
multiple genes (i.e., what we inherit), the environment (i.e., where
and how we live), and interactions between the two. Defining
precisely which genes and environmental factors are involved and how
they interact in the development of alcohol use problems are complex
tasks. Fortunately, a number of major technological advances are
helping investigators make significant progress toward this goal.
The alcoholism-related interactions explored in this issue of
Alcohol Alert occur within settings ranging from brain cells to
city streets.
Alcohol and the Brain
All brain functions, including addiction, involve communication
among nerve cells (i.e., neurons) in the brain. This communication
involves both a "sending" neuron and a "receiving neuron" that
communicate across minute gaps
between them called synapses. Messages are carried across synapses
by chemicals called neurotransmitters. Alcohol causes many of its
physical effects (e.g., intoxication and sleepiness) by affecting
communication between neurons.
After its release, a neurotransmitter crosses the synapse and
activates a receptor protein in the receiving neuron. Activating a
receptor can cause the receiving neuron to change or adapt.
Prolonged or repeated exposure to alcohol can cause such changes in
neurons that in susceptible people can lead to the development of
alcoholism. Adaptation to the presence of alcohol is also thought to
underlie such phenomena as tolerance, withdrawal, and the persistent
craving for alcohol that has been postulated to provoke relapse.
Measuring Neuronal Activity
The communication between neurons creates electrical activity.
Groups of neurons with similar functions extend from one brain
region to another, forming neural circuits. Circuits interact with
one another to integrate the functions of the brain, including
complex emotional, cognitive, and motivational processes. To
understand the link between alcohol use and these complex processes,
alcohol researchers needed a way to relate the chemistry of
individual neurons to the integrated activity of neuronal circuits.
A recent approach to the problem involves the simultaneous
measurement of electrical activity within selected neuronal
circuits. This technique has been used in both rats and humans. For
example, in a preliminary study, Woodward and colleagues (1) used
this technique to trace the sequence of neuronal activity in rats as
they responded to the presence of alcohol. This technique has also
been applied to human studies using electroencephalography (EEG).
Researchers have identified at least three brainwave patterns with
EEG that have been associated with alcoholism and which may help
experimenters identify people at increased risk (2-6).
Alcoholism and Genetics
The blueprint for the human body is encoded in its genes. Genes
govern the expression of specific genetic traits and account for
trait differences that help distinguish one individual from another.
Each gene directs the synthesis of a different protein. Abnormal
gene variants may give rise to defective proteins that can
contribute to disease. Vulnerability to complex diseases like
alcoholism requires changes in multiple genes. Because genetics
studies indicate that between 40 and 60 percent of alcoholism
vulnerability has a genetic basis (7), finding the genes that are
involved in alcoholism vulnerability is a high priority for alcohol
research. Genetics studies, such as the Collaborative Study on the
Genetics of Alcoholism, have already identified several sites in the
brain where the genes for alcoholism may be located. The map of the
human genome will no doubt help lead investigators to the discovery
of the genes that play a role in increasing an individual's
vulnerability to alcoholism.
In search for the genes for alcoholism, alcohol investigators are
taking full advantage of the new genetic engineering techniques. For
example, researchers can inactivate, or knock out, a gene, creating
a line of mice that lack a particular receptor or other protein
thought to influence a specific genetic trait. Conversely,
scientists can insert an additional gene into an animal's genetic
material (8,9). Animals with an added gene are called transgenic.
The response of the genetically engineered animal to alcohol can be
compared with that of a genetically unaltered animal to help
determine the role of the gene in mediating a particular
alcohol-induced behavior (e.g., incoordination) (10,11).
Of the many different knockouts, at least three have implicated
brain proteins involved in high alcohol preference in mice (12-14).
Knockout (15-17) and transgenic (15,18) experiments also have
implicated some of the same receptors and brain proteins in both
sensitivity and preference to alcohol. In the animal experiments,
mice that initially display high resistance (i.e., are less
sensitive) to alcohol-induced sedation usually develop a high
preference for alcohol consumption. These laboratory findings are
consistent with Schuckit's (19) observation that low sensitivity to
alcohol may predict future development of alcoholism. If these
results are confirmed in humans, they may provide a means to help
identify high-risk youth for targeted intervention programs.
The use of microarrays is another powerful new technology in
alcoholism research. This technique permits the simultaneous study
of many genes and provides scientists with new power to understand
changes in gene expression that relate to the vulnerability to
developing alcoholism. The long-term adaptation of the brain's
neurons to alcohol may result, in part, from changes in gene
function (20). Genes direct the synthesis of proteins, such as
receptors. A gene's level of activity, therefore, can be used to
obtain indirect information about its proteins .
Because alcohol is known to affect gene-induced protein
production (i.e., gene expression) (21), levels of genetic activity
can be tracked to determine how genes associated with an
alcohol-induced effect are expressed. Tracking the activity of a
single gene takes time; given the large number of genes that may be
involved in producing alcohol's effects, the task of linking
specific genes to specific effects might be formidable. However, by
using microarrays, alcohol scientists can track up to 10,000
selected genes simultaneously. In this approach, the genes of
interest are affixed to a glass slide, silicon chip, or similar
surface--often as small as a postage stamp--forming a so-called
microarray. An automated operating system scans the microarray and
can calculate the relative expression levels of up to 10,000
selected genes simultaneously (22). As more alcoholism researchers
begin to employ this procedure, it may become possible to identify
virtually every gene and its protein that play a significant role in
alcohol-related behavior.
Alcoholism Treatment
Developing a reliable biological marker of recent alcohol
consumption has long been on the "wish list" of alcohol researchers
and clinicians alike. Such markers could enable researchers to
confirm self-reported drinking behavior by study participants and
could help clinicians monitor patients undergoing alcoholism
treatment. Most currently available markers (e.g., gamma-glutamyl
transferase) are alterations in blood chemistry that can be induced
directly or indirectly by alcohol. However, many of the markers lack
specificity (i.e., altered marker levels are not necessarily the
result of alcohol consumption) or sensitivity (i.e., altered marker
levels are difficult to detect at low levels of consumption). In
addition, some marker levels are not useful until serious
alcohol-related organ damage has occurred (23,24).
Carbohydrate-deficient transferrin (CDT) is a blood protein that
increases in concentration after alcohol consumption has exceeded
approximately five standard drinks (i.e., 60 grams) per day for 2 to
3 weeks (25). CDT concentrations then remain elevated for up to 2
weeks after drinking ceases, potentially enabling relatively early
detection of relapse among alcoholics in treatment (26). Interest in
using CDT as a biological marker of alcohol consumption has
increased because of its relatively high sensitivity and
specificity. Research is underway to improve the precision of CDT
measurement (27,28). A kit designed to measure CDT levels in
patients will soon be commercially available for clinical use.
Geocoding: Mapping Environmental Influences in Drinking Behavior
The problems caused by alcohol are influenced by a variety of
cultural, demographic, and social factors that may differ
significantly between geographic areas (29,30). Geocoding is the
process of associating descriptive data to fixed geographic points
for the purpose of correlating events with where and when they take
place (30). For example, Gruenewald and colleagues (31) used
geocoding to relate the availability of alcohol in different
communities to local rates of single-vehicle nighttime crashes, a
measure thought to reflect rates of drinking and driving. Major
advances in computer science now permit the results of geocoding to
be analyzed statistically and displayed clearly in maps that can be
linked to data available from the U.S. Bureau of the Census and
other sources (31). As research in this area matures,
alcohol-related geocoding research could become a useful guide to
social policy.
From Genes to Geography: The Cutting Edge of Alcohol Research—A
Commentary by NIAAA Director Enoch Gordis, M.D.
The advances described in this Alcohol Alert offer a
glimpse of the way in which cutting-edge technology is being used by
alcohol scientists to undertake complex studies more quickly and
with greater efficiency. We share this glimpse with our readers for
two important reasons. First, much of what we have learned in recent
years about alcohol and the brain and the genetic basis of alcohol
dependency would not have even been possible without the type of
technological capability available to scientists today. The more we
understand about the mechanisms of dependence, the more likely it is
that we can design effective prevention and treatment. Second, many
of us tend to think of technology only in terms of basic research.
However, it is equally important to understand that technology also
contributes to other important arenas of the alcohol use problems
field, such as policy analysis, prevention planning, and clinical
practice.
Acknowledgments
The National Institute on Alcohol Abuse and Alcoholism wishes to
acknowledge the following individuals who have contributed their
time and expertise to the development of the Alcohol Alert
series during the past 2 years: John Doria; Mary Dufour, M.D.,
M.P.H.; Michael Eckardt, Ph.D.; Richard Fuller, M.D.; David Goldman,
M.D.; Brenda Hewitt; Daniel Hommer, M.D.; William Lands, Ph.D.;
Susan Martin, Ph.D.; Diane Miller; Antonio Noronha, Ph.D.; Eve
Shapiro; Kenneth Warren, Ph.D.; Dianne Welsh; Ellen Witt, Ph.D.; and
Sam Zakhari, Ph.D.
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NIAAA
Copies of the Alcohol Alert are available free of charge
from the
National Institute on Alcohol Abuse and Alcoholism Publications
Distribution Center
P.O. Box 10686, Rockville, MD 20849–0686.
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