Genetics and alcohol-induced inflammation appear to combinein complex ways to cause dependency, but in rats, at least,exercise reduces long-term damage to the brain.
Rats that drink like college students at a frat party are teaching researchersabout how alcohol affects the growth and death of brain cellsand 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 geneticsand inflammation, Said Fulton Crews, Ph.D., a professor of pharmacologyand psychiatry and director of the Bowles Center for AlcoholStudies at the University of North Carolina at Chapel Hill.
Crews delivered the annual Mark Keller Honorary Lecture at theNational Institute on Alcohol Abuse and Alcoholism in November.
His alcoholism research for several decades has been based onthe fact that neural stem cells continue dividing in adulthoodand give rise to new neurons in the dentate gyrus of the hippocampusand the subventricular zone of the anterior lateral ventricles.
However, ethanol blocks development of new adult neurons, decreasingneural stem cell proliferation, reducing cell survival, andaltering maturation of new neurons. Part of that effect is dueto genetics, since rats bred to prefer alcohol exhibit greaterbrain damage after drinking than do controls.
Age is another factor. Adolescent rats are less sensitive tothe intoxicating effects of alcohol, but are more likely tosustain brain damage.
A family history of alcoholism and lower age at drinking onsetare known to increase the prevalence of alcohol dependence,said Crews. Adolescent rats show more damage in the forebrainfrom alcohol, and other studies have shown that damage in theorbitofrontal cortex leads to maladaptive decision making.
Crews' recent research has concentrated on how immune regulatoryand transcription factors affect neurogenesis. For instance,CREB (cAMP response element-binding) proteins are transcriptionfactors that increase or decrease the transcription of certaingenes. Given the equivalent of binge-drinking doses of alcohol,rats show a dose-dependent decrease in CREB binding, which protectsneurons, and an increase in necrosis factor-kB (NF-kB) DNA binding activity,a proinflammatory agent.
"Ethanol intoxication decreases neurogenesis, and cell deathoccurs during intoxication, not withdrawal," said Crews.
Crews and his colleagues also found that butylated hydroxytoluene (BHT)—anantioxidant used as a food preservative— blocks tumor necrosisfactor-a (TNF-a), an inflammatory cytokine, in brain slice cultures andin vivo by blocking NF-k B activation. That observation ledthem to look more closely at the effects of inflammation. GivingBHT with ethanol produced some reversal of neuronal death bysuppressing the inflammatory reaction, leading Crews to speculateabout whether diet plays a role in this process. Perhaps theBHT—much reviled by health-food advocates—might protectneurogenesis.
"Natural foods may not be as good for you in this case," he joked.
To test the role of TNF-a, he gave rats a dose of lipopolysaccheride,a bacterial toxin that produces inflammation. inan hour, the toxin produced a 1,000-fold increase in TNF-a inliver, serum, and brain. Levels in liver and serum dropped withinhours, but brain levels stayed up, said Crews.
"Cytokines stay in the brain a long time," said Crews. "Tenmonths after a single dose of the toxin, brain levels remained high."Further study found that alcohol potentiated the toxin's effect inproducing long-lasting effects of TNF-a, indicating a similarpathway. At the same time, alcohol also reduces brain levelsof IL-10, an anti-inflammatory cytokine.
In another experiment, rats given high doses of alcohol forfour days exhibited cognitive deficits associated with neurotoxicityin the dentate gyrus, which is involved with memory and learning.In a water-maze test, both control and alcohol-drinking ratslearned equally well, but even three weeks into abstinence thealcoholic rats were much worse at relearning the task. Theykept making the same mistake over and over again.
"Such perseveration in rats only brings to light how difficult therapyis for the human alcoholic," said crews. "They have to regenerateto relearn."
The implication, said Crews, is that neurons must be regeneratedto provide a substrate for recovery. Yet that does seem possibleonce 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 executivefunction, how do we make the brain grow?"
Crews has an answer for the rats and maybe for humans, one thatdoesn't even require approval by the Food and Drug Administration.Heavy physical exercise is known to increase neurogenesis, hesaid, so he and his colleagues tried an experiment with threegroups 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 runningincreased neurogenesis equally in both the water-drinking ratsand the exercising, alcoholic animals, he said. Perhaps an exerciseregimen could reverse neurodegeneration, improve executive function,and help alcoholics along the path to recovery.
"Therapists should challenge their patients to engage in vigorous physicalexercise and see if it helps recovery," he said.
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