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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 blood–brain 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 Koob.
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 signaling.
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 brain—one 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 forebrain—particularly
the nucleus accumbens and the amygdala—create 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
effects—from 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 others—probably
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 the opposite.
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 normal—they 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-points—an 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 overdrink—a 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 therapy—whether
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."
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