How alcohol gives, and then takes away

November 13, 1999

Mental diseases, including addiction and alcohol dependence, may indeed be "all in your head." But not in the way you might think. Researchers have learned that alcohol may be particularly damaging to the brain's reward pathways, specifically dopamine and serotonin neurons. This damage -- a sensitization of the neurons to a process called excessive excitation or "excitotoxicity" through the N-methyl-D-aspartate (NMDA) glutamate receptor -- could be an important component in transitioning from experimentation to addiction. However, researchers may have also discovered that a brain growth hormone called Brain Derived Neurotrophic Factor (BDNF) may be able to protect neurons against this excitotoxicity.

"If dopamine and serotonin neurons are damaged," said Fulton T. Crews, Director of the Center for Alcohol Studies, University of North Carolina, "this would disrupt reward processes in ways that could contribute to addiction." Crews, lead author of a study recently published in the November edition of Alcoholism: Clinical & Experimental Research, explained that his findings are related to what is called a "reward deficiency hypothesis" of addiction.

The "reward deficiency syndrome" links addictive, compulsive or impulsive disorders -- such as alcoholism, substance abuse, smoking, compulsive overeating and obesity, attention-deficit disorder, Tourette's syndrome and pathological gambling -- with a "chemical imbalance" in the brain. Researchers knew that pleasure, to various degrees, is a distinct neurological function that is linked to a complex reward and reinforcement system. In particular, dopamine appears to be a primary neurotransmitter of reward in the nucleus accumbens and hippocampus areas of the brain. Serotonin is believed to have an additive or synergistic effect on dopamine. Alcohol is known to initially lead to an increase in dopamine release, which supposedly enhances reward/pleasure. However, chronic and/or high levels of alcohol will eventually lead to a decrease in dopamine release. This disruption of intercellular interactions or "chemical imbalance" can result in negative feelings such as anxiety, anger or in a craving for a substance, such as alcohol, that can alleviate the negative feelings. Yet because chronic drinking releases a continuously reduced amount of dopamine, more and more alcohol is needed to feel "normal."

"Science has come to the realization that what alcohol may be doing," said Boris Tabakoff, Chairman of the Department of Pharmacology, University of Colorado School of Medicine, "is what I call 'downregulating' dopamine systems. This study shows that downregulation may actually be a result of neuronal damage. Alcohol leads to a sensitization to glutamate, the glutamate produces the damage, and the damage results in a lower function of the dopamine system."

"This is important," added Tabakoff, "because it provides an explanation for why individuals may not be able to control their drinking because of biological factors. If the neurons are damaged, they can keep trying to use alcohol to attain some level of pleasure, but they'll never be able to do it."

Although there is no such thing as a specific gene for alcoholism, there does seem to be a "genetic predisposition" to the development of alcoholism. Tabakoff spoke of one study in which 20 to 28 percent of individuals, who had at least one parent who was alcoholic, who went on to develop alcoholism themselves. Normally, among those who have no familial history of alcoholism, around eight to 10 percent develop alcoholism. In short, those with a family history of alcoholism seem to have a two to three time's greater chance of developing the disease. Although the exact role of biology in alcoholism has not yet been determined, research findings support both discovery as well as optimism.

"This is one of the first studies to show a relationship between excitotoxicity, which likely occurs during ethanol withdrawal, and NMDA receptors," said Richard A. Morrisett, Associate Professor of Pharmacology at The University of Texas at Austin. " But it is the first to show that BDNF can actually protect against this. The rescue or prevention of cell death is probably one of the most important aspects of this study."

"Clearly the future direction of this area of study is medication development and an understanding of protective factors," said Tabakoff. "If you have an individual who is drinking a lot but decides to stop, you need to treat them with something more than moral support as the very process of withdrawal could damage the neurons." Tabakoff spoke of developing drugs that will protect the neurons, returning the individuals' pleasure systems to normal while avoiding irrevocable damage.

Morrisett indicated there is a need for future studies that look at the effects of lower levels of alcohol on excitotoxicity. "The levels used in this study, 100 mM, are five times the legal levels of intoxication," he said. "I would like to see what occurs at 20mM, because that's more related to when we start to drink, when we may start to become dependent." When a person starts to drink and is experiencing the reinforcing aspects, he said, that's when "we're having a little engine misfire." At the point of full-blown alcoholism, he said, "we're addicted, we're dependent, we're drinking fifths of whiskey a day, the car is wrecked."

Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Heather G. Waage, Mary Beth Wilkie, and Jean M. Lauder of the Center for Alcohol Studies, University of North Carolina. The study was funded by the National Institute on Alcohol Abuse and Alcoholism.
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Alcoholism: Clinical & Experimental Research

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