Untangling the matrix of risk factors for alcoholism

July 15, 2001

Children of alcoholics (COAs) have a high risk of developing alcoholism, simply by virtue of their family history of alcoholism. Many studies have found that COAs also tend to exhibit high levels of behavioral and emotional problems. In the July issue of Alcoholism: Clinical & Experimental Research, researchers explore the biochemical basis of two aspects of 'behaviors of undercontrol.' Their findings indicate that behavioral disinhibition (BD), such as impulsive aggression, and negative affect (NA), such as depression and anxiety, may be genetically influenced through the regulation of a neurotransmitter called serotonin (5-HT).

"Serotonin's primary role appears to be that of an inhibitor," explained Geoffrey R. Twitchell, Postdoctoral Fellow at the UCLA Integrated Substance Abuse Programs and lead author of the study. "Dysfunction in 5-HT neurotransmission has been found in individuals who exhibit problems with behavioral and affective control.

For example, 5-HT deficits have been observed in antisocial alcoholics who exhibit BD, such as aggressiveness and difficulty controlling alcohol consumption. The relationship between 5-HT dysfunction and impulsive aggression in non-alcoholic groups has also been reliably documented. In addition, many studies have found 5-HT dysfunction in individuals who exhibit increased NA, as indicated by depression and anxiety. Depressed and highly anxious individuals are often treated with 5-HT enhancing medications such as selective serotonergic reuptake inhibitors."

"Exactly how a serotonergic dysfunction relates to BD and NA is the realm of great speculation," commented Robert O. Pihl, professor of psychology and psychiatry at McGill University. "Because serotonergic dysfunction seems related to an exceedingly wide range of behaviors, a likely explanation is that of a regulatory role for many biochemical systems in the brain. A speculative analogy has serotonin acting much like the maestro of an orchestra, able to meld disparate sections in order to produce music rather than cacophonous noise. Thus, without appropriate modulation - which we assume is supplied by serotonin - individuals will overreact to emotional stimuli."

Knowing of the strong association between serotonergic dysfunction and behavioral disorders such as alcoholism, aggressiveness and depression, researchers wanted to further examine genetic variations in the serotonin transporter gene (5-HTTLPR). Genetic variation in 5-HTTLPR is related to efficiency in 5-HT reuptake, one aspect of 5-HT functioning. The long (LL) variation or genotype has been associated with an increased number and function of 5-HT transporters (the 5-HT structure that recycles synaptic 5-HT back into the pre-synaptic neuron) when compared to the short (SS) or the short/long (SL) genotypes. An increased functionality of the 5-HT transporter has the effect of reducing the amount of 5-HT available in the synapse. Decreased synaptic 5-HT has the effect of decreasing overall 5-HT functioning.

Some psychiatric genetic studies had previously documented a relationship between the SS variant of 5-HTTLPR and alcohol dependence, depression, anxiety, and the personality trait neuroticism (which is also a marker of NA).

Some studies of alcoholics, however, have found a relationship between the LL variant of 5-HTTLPR and low levels of response to alcohol, alcohol dependence, and antisocial alcoholism. For the current study, researchers examined 47 families classified by the fathers' alcoholism subtype. (The data were taken from a larger, ongoing longitudinal family study on risks for developing alcoholism and other problems.)

The authors found that the LL genotype of 5-HTTLPR was associated with both BD and NA in COAs. In addition, significantly more LL than SS/SL genotype children reported they had already consumed alcohol.

"This finding," said Twitchell, "supports the hypothesis that behavioral and emotional problems in COAs, which put them at increased risk for later development of alcoholism, may be genetically regulated in part by the 5-HT transporter. In other words, the 5-HTTLPR genotype may serve as a marker for vulnerability for COAs.

"The results of this study are fascinating," said Pihl. "Although we have learned to cautiously view genetic studies that attempt to explain behavior; this one makes sense. It suggests an overactive transporter gene which could result in a deficiency of serotonergic synaptic functioning. This is another strong piece of evidence in this evolving story. However," he added, "there remain gaps in our knowledge. We continue to be in a state much like what Newton described when he said 'we are finding interesting pebbles while the great ocean of truth lays undiscovered before us.'"

Twitchell hopes to move beyond those 'pebbles' one day. "Our group plans to follow these children over time with complete psychosocial assessments at three-year intervals into adulthood," he said. "Our finding of higher rates of alcohol consumption in LL genotype children as young as a mean age of 10.88 years is important because it suggests that this liability manifests early in one's life course. Those with a family history of alcoholism may want to be aware of their increased risk and monitor their alcohol use accordingly."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Gregory L. Hanna, Scott F. Stoltenberg, and Robert A. Zucker of the Departments of Psychiatry and Psychology, and the Alcohol Research Center, at the University of Michigan; Edwin H. Cook of the Laboratory of Developmental Neuroscience in the Department of Psychiatry at the University of Chicago; and Hiram E. Fitzgerald of the Department of Psychology at Michigan State University.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism, Michigan State University, the University of Michigan Alcohol Research Center, and the National Institute on Drug Abuse.

Add'l Contact: Robert O. Pihl, Ph.D.
McGill University
Alcoholism: Clinical & Experimental Research

Alcoholism: Clinical & Experimental Research

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