One Night in San Diego:
Tragedy of Alcohol Abuse Drives TSRI Researcher's Work
By Jason Socrates Bardi
which hath made them drunk hath made me bold;
What hath quench'd them hath given me fire.
Act II, scene 2
An affluent man in his 60s, drunk, pushes past his pleading wife, gets
in his late model Cadillac, guns it out of the gas station where the two
have been fighting over the keys, and drives the wrong way up the freeway
off ramp, running head-on into a car, killing the driver, and injuring
At around the same time, a prominent member of a San Diego community,
blind-drunk, crashes his family minivan into several parked cars along
his street. Nobody is hurt, but after the story breaks, he will be forced
A few hours later, some teenagers are drinking and blasting around in
their old Ford pickup truck. A momentary lapse or some loose gravel and
they plunge off the road and down a canyon. Luckily, they are not hurt,
but they have to wait until morning before an emergency crew can climb
down and haul them out.
According to The Scripps Research Institute (TSRI) Neuropharmacology
Professor George F. Koob, these three storiesbased on actual events
that transpired on a single night in San Diego last yearhighlight
how problems related to alcohol cut across nearly all social, financial,
and age-related strata.
Koob has been studying the neurobiology of alcohol and alcoholism for
several years, and he has developed models of normal and excessive drinking
to study the neurophysiological correlates of alcohol consumption. His
studies start with the brain and the neurobiology of alcohol in the brainsome
of which we understand, and some of which is only now coming to light.
"Despite many years of independent study of the biochemistry, physiology,
systems, and processes hypothesized to be involved in alcoholism, the
mechanisms are still unclear," says Koob.
An Enigma in a Bottle
Of all the legal and illegal drugs, alcohol is both one of the most
readily available and one of the most toxic. It holds an enigmatic place
in American society.
On the one hand, alcohol is regularly or occasionally consumed in various
forms by nearly two thirds of all American adults, and there are few who
have not consumed alcohol on occasion. According to United States Centers
for Disease Control and Prevention statistics, four fifths of the U.S.
adult population have been regular or occasional drinkers at one time.
Alcohol is the great "social lubricant" that humans have imbibed for
at least 7,000 years (the age of the oldest known wine jugs ever found
by archeologists). The Egyptians loved wine so much that they imported
grapes. The Greeks celebrated the joys of inebriation through their god
of wine, Dionysus. The Romans called the same god Bacchus.
On the other hand, alcohol extracts a heavy toll on society.
Drunk driving is a major scourge in the United Statesabout a third
of the approximately 40,000 traffic fatalities every year involve drunk
drivers. Thousands more die each year from accidental or deliberate alcohol
poisoning, and from alcohol-related degenerative conditions like gastritis,
cardiomyopathy, and liver disease. In 1999, according to the Centers for
Disease Control and Prevention (CDC), a total of 19,171 persons in the
United States died from such causes. And fetal alcohol syndrome, caused
by alcohol consumption by pregnant women, is the leading cause of mental
retardation in the United States. The CDC estimates that as high as one
out of every thousand babies born in the United States each year suffers
from fetal alcohol syndrome, and they report that the heath costs related
to these children was $1.9 billion in 1992the last year for which
they report such statistics.
One of the most terrible costs of excessive drinking is, of course,
alcoholismthe chronic compulsive use of and loss of control over
alcohol intake. For reasons that are not entirely clear, some portion
of the people who drink suffer from some form of alcoholism.
In addition to its enormous toll on families and society at large, alcoholism
is devastating to an individual's health because of the damage that excessive
amounts of alcohol cause to the system over time. Whether it is the liver
or the heart or some other organ, says Koob, "Ultimately, alcoholism gets
you as some part of your body goes."
The direct and indirect public health costs of alcoholism are estimated
to be in the hundreds of billions of dollars yearly. Currently, there
is no cure for alcoholism, and the neurobiology of the disease is not
"Why does 10 to 15 percent of the population become alcoholic and the
rest of the population does not?" asks Koob. "For instance, we know that
the children of alcoholics are four to five times more likely to become
alcoholics themselves, but we do not know what the neurological basis
for this trait is."
A Consortium Seeks Answers
Last year, the National Institute on Alcohol Abuse and Alcoholism (NIAAA)
funded a multi-year consortium headed by Koob to identify the molecular
basis of alcoholism. The aim of the Integrative Neuroscience Initiative
on Alcoholism consortium grant is to address the basic science of alcoholism
and to establish a platform upon which future treatments can be built.
The grant supports the combination of physiological, molecular, and
cellular models to derive the genetic and environmental factors that form
the basis for individual differences in developing excessive drinking.
A large portion of the funding is dedicated to setting up shared facilities
to centralize and enhance some of the tasks common to the researchers
with independently funded research projects.
"The goal is to figure out what makes people vulnerable to excessive
drinking," says Koob. "What is the genetic loading and how does that interact
with environmental determinants?"
A neuroinformatics group, for instance, will make use of the newly solved
human and the soon-to-be-completed mouse genomes to interpret "gene chip"
screens needed to identify the genes involved. Certain gene clusters are
regulated by alcohol and may be differentially regulated during the development
of excessive drinking.
Another group will establish animal models of alcoholism that will be
used to study these genes in action.
The Effects of Alcohol on the Brain
Scientists used to think of alcohol as a membrane disruptor with a generalized
effect all over the brain, as the small molecule can freely diffuse across
the bloodbrain barrier. They now know that there are particular
cells in the brain that alcohol targets by binding certain hydrophobic
pockets on their surface receptors. The gamma-aminobutyric acid (GABA)
receptor is one of these. "Alcohol is an indirect GABA agonist," says
GABA is the major inhibitory neurotransmitter in the brain, and GABA-like
drugs are used to suppress spasms. Alcohol is believed to mimic GABA's
effect in the brain, binding to GABA receptors and inhibiting neuronal
Alcohol also inhibits the major excitatory neurotransmitter, glutamate,
particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor. And
it releases other inhibitors, such as dopamine and serotonin. Consumption
of even small amounts of alcohol increases the amount of dopamine in the
nucleus accumbens area of the brainone of the so-called "reward
centers." However, it is most likely that the GABA and glutamate receptors
in some of the reward centers of the basal forebrainparticularly
the nucleus accumbens and the amygdalacreate a system of positive
reinforcement. In fact, multiple neurotransmitters in various parts of
the brain combine to make the consumption of small doses of alcohol enjoyable.
"Alcohol tends to activate the whole reward system," says Koob, who
is particularly interested in the effects of alcohol in the amygdala.
The neurochemical effects of alcohol cause a range of short-term effectsfrom
a mild buzz to slow reaction times, which make drunk driving so dangerous.
In the long term, these effects are also the basis for two of the defining
characteristics of addiction: tolerance and dependence.
Tolerance and Overdrinking
Tolerance to alcohol is one aspect of alcoholism that leads to overdrinking.
Tolerance can be acute, in one bout of drinking, or long-term, requiring
an ever-larger dose to get the same effect over time.
The effect of acute tolerance is a common experience for anyone who
has had more than a few drinks. Initially, the first drink has a relaxing
effect, but as a person continues drinking, it takes more and more alcohol
to produce the same effect. Some people have more acute tolerance than
othersprobably due to genetic factors. "These are the people who
can drink anybody else under the table," says Koob. He adds that these
people may also be at increased risk of developing dependence on alcohol
because of their increased tolerance.
Dependence to alcohol is linked to the interaction of alcohol with the
brain's stress system, which alcohol activates. The major component of
the brain stress system is the corticotropin-releasing factor (CRF) in
the amygdala and related areas, which activates sympathetic and behavioral
responses to stress. A normal stress response sees CRF recruiting other
parts of the brain to help adapt the mind and body to deal with the physical
and mental "stressors" that challenge it. Alcohol interacts in such a
way as to acutely reduce CRF levels in the brain; chronic alcoholism does
Koob hypothesizes that there also may be individuals who are at increased
risk of becoming alcoholics because their genetic makeup causes them to
have higher CRF levels than normal.
"They may be drinking to feel normalthey may drink to tame a hyperactive
CRF stress system in the brain," he says.
Unfortunately, CRF and the stress system adjust to the alcohol. CRF
is hypothesized to persist at artificially high levels in the brain while
reward neurotransmitters are compromised. In alcoholism, the effect is
even more pronounced and results in an equilibration of neurotransmitter
levels at artificial, "allostatic" set-pointsan equilibration driven
by chronic alcohol ingestion. In the absence of alcohol, the alcoholic
feels ill because his or her body cannot easily reverse these artificial
levels (for example, high CRF and low reward neurotransmission).
This ill feeling may contribute to the tendency of the alcoholic to
overdrinka danger because of the toxic effect on the brain and body
of subjecting oneself to so much alcohol.
Sadly, the brain often does not perceive the consequences of the short-term
relief that the alcohol brings. When a person overdrinks, there is depleted
GABA function in the brain and also, possibly, a hyper-excitable glutamate
system. Alcoholics feel good while they are boozing. However, this short-term
relief makes the whole system worse off.
Understanding Stress is Important for Treatment
Not only is stress part of the spiral disregulation of motivational
processes involved in the development of alcoholism, but stress is one
of the most common states associated with relapse. Relapse also occurs
as a consequence of behavioral patterns, such as walking by the old saloon
or hanging around with familiar drinking buddies. "Before you know it,
you're back into it," says Koob.
Alcoholics drink when they're happy, alcoholics drink when they're sad,
and they drink when they are stressed. "Any excuse to drink," he says.
In the treatment of alcoholism, a person is especially vulnerable to
relapse for a year to 18 months after cessation of drinking, a period
Koob refers to as "protracted abstinence." One of Koob's research interests
is in protracted abstinence and the residual changes in the brain that
take place during it.
These are very important studies because behavior plays such a large
role in relapse, and behavioral therapy is a prominent part of the recovery
process. Most alcoholism treatment programs involve some form of behavioral
therapywhether through professional counseling or a group like Alcoholics
Anonymous. The goal of much of Koob's work is to someday help individuals
who have become addicted to alcohol.
"It's very possible that we are going to find brain areas that code
for certain proteins responsible for the individual differences that make
15 percent of the population vulnerable to alcoholism and/or that protect
85 percent," says Koob.
"Once we know the circuits and the basis for alcoholism, we can develop
new targeted treatments."
|Horizontal section of a rat brain depicting the principal structures
of the extended amygdala. These include the central nucleus of the
amygdala, the shell part of the nucleus accumbens, and the bed nucleus
of the stria terminalis. The drugs listed below each structure refer
to potential sites of action of drug reinforcement during the addiction
cycle, either positive or negative.
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