Rats that drink like college students at a frat party are teaching
researchers about how alcohol affects the growth and death of brain cells and
providing insight into how alcohol produces addictive behavior. They may even
point to ways to help alcoholics reach sobriety.
Alcohol's effects on the brain occur through a mixture of genetics and
inflammation, Said Fulton Crews, Ph.D., a professor of pharmacology and
psychiatry and director of the Bowles Center for Alcohol Studies at the
University of North Carolina at Chapel Hill.
Crews delivered the annual Mark Keller Honorary Lecture at the National
Institute on Alcohol Abuse and Alcoholism in November.
His alcoholism research for several decades has been based on the fact that
neural stem cells continue dividing in adulthood and give rise to new neurons
in the dentate gyrus of the hippocampus and the subventricular zone of the
anterior lateral ventricles.
However, ethanol blocks development of new adult neurons, decreasing neural
stem cell proliferation, reducing cell survival, and altering maturation of
new neurons. Part of that effect is due to genetics, since rats bred to prefer
alcohol exhibit greater brain damage after drinking than do controls.
Age is another factor. Adolescent rats are less sensitive to the
intoxicating effects of alcohol, but are more likely to sustain brain
A family history of alcoholism and lower age at drinking onset are known to
increase the prevalence of alcohol dependence, said Crews. Adolescent rats
show more damage in the forebrain from alcohol, and other studies have shown
that damage in the orbitofrontal cortex leads to maladaptive decision
Crews' recent research has concentrated on how immune regulatory and
transcription factors affect neurogenesis. For instance, CREB (cAMP response
element-binding) proteins are transcription factors that increase or decrease
the transcription of certain genes. Given the equivalent of binge-drinking
doses of alcohol, rats show a dose-dependent decrease in CREB binding, which
protects neurons, and an increase in necrosis factor-kB (NF-kB) DNA binding
activity, a proinflammatory agent.
"Ethanol intoxication decreases neurogenesis, and cell death occurs
during intoxication, not withdrawal," said Crews.
Crews and his colleagues also found that butylated hydroxytoluene
(BHT)—an antioxidant used as a food preservative— blocks tumor
necrosis factor-a (TNF-a), an inflammatory cytokine, in brain slice cultures
and in vivo by blocking NF-k B activation. That observation led them to look
more closely at the effects of inflammation. Giving BHT with ethanol produced
some reversal of neuronal death by suppressing the inflammatory reaction,
leading Crews to speculate about whether diet plays a role in this process.
Perhaps the BHT—much reviled by health-food advocates—might
"Natural foods may not be as good for you in this case," he
To test the role of TNF-a, he gave rats a dose of lipopolysaccheride, a
bacterial toxin that produces inflammation (see
FIG1). in an hour, the toxin
produced a 1,000-fold increase in TNF-a in liver, serum, and brain. Levels in
liver and serum dropped within hours, but brain levels stayed up, said
"Cytokines stay in the brain a long time," said Crews."
Ten months after a single dose of the toxin, brain levels remained
high." Further study found that alcohol potentiated the toxin's effect
in producing long-lasting effects of TNF-a, indicating a similar pathway. At
the same time, alcohol also reduces brain levels of IL-10, an
In another experiment, rats given high doses of alcohol for four days
exhibited cognitive deficits associated with neurotoxicity in the dentate
gyrus, which is involved with memory and learning. In a water-maze test, both
control and alcohol-drinking rats learned equally well, but even three weeks
into abstinence the alcoholic rats were much worse at relearning the task.
They kept making the same mistake over and over again.
"Such perseveration in rats only brings to light how difficult
therapy is for the human alcoholic," said crews. "They have to
regenerate to relearn."
The implication, said Crews, is that neurons must be regenerated to provide
a substrate for recovery. Yet that does seem possible once the extended,
harmful inflammatory effects of alcohol fade.
"Within 20 weeks of stopping alcohol, the damage can be
reversed," he said. "So if brain regrowth is useful for the return
of executive function, how do we make the brain grow?"
Crews has an answer for the rats and maybe for humans, one that doesn't
even require approval by the Food and Drug Administration. Heavy physical
exercise is known to increase neurogenesis, he said, so he and his colleagues
tried an experiment with three groups of rats. One group drank alcohol, but
got no exercise. A second drank water and exercised.
"The third drank huge amounts of alcohol and also ran huge
amounts," said Crews. The sedentary, alcoholic rats lost neurons, but
running increased neurogenesis equally in both the water-drinking rats and the
exercising, alcoholic animals, he said. Perhaps an exercise regimen could
reverse neurodegeneration, improve executive function, and help alcoholics
along the path to recovery.
"Therapists should challenge their patients to engage in vigorous
physical exercise and see if it helps recovery," he said.