Researchers are now integrating the fields of genetics and neurobiology to investigate how genetic influences may alter the function of neurotransmitters prior to and during the development of alcoholism. “We’re now in an era where we’ve come to appreciate the individuality of vulnerability and treatment response,” noted David Goldman, MD, Chief of the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism. “We’ve also come to appreciate that an important component of this clinical individuality and of human individuality are the inherited differences.”

BEHAVIOR AND THE ORIGINS OF DIFFERENTIAL VULNERABILITY

In the April issue of Alcoholism: Clinical & Experimental Research, Dr. Goldman reported the results of a meta-analysis study in which he and his colleagues examined the correlation between central serotonergic neurotransmission and three behavior patterns that are relevant for alcoholism: disinhibition (impulsive aggression), negative mood states (such as anxiety and depression), and a low response to alcohol. The neurotransmitter is very likely influenced by genetics and early stress experiences, as well as alcohol itself, the authors wrote. Serotonergic dysfunction has been linked to a number of psychiatric disorders, as well as the development and maintenance of excessive alcohol consumption and alcoholism. The researchers also considered the genetic influences, the biologic substrate or tendencies inherent to a person, and the secondary changes that alcohol induces in the function of the neurotransmitter system. In addition, they examined the possible consequences of both the inherited differences and the secondary changes that affect behavior and vulnerability to alcoholism.

Serotonin is a neurotransmitter that is protean in its underlying effects on many aspects of basic semantic function, explained Dr. Goldman. Serotonin plays a role in temperature control and sleep and also affects impulse control and behavior inhibition. Circuits that depend on serotonin are also vital to a person’s sense of well-being and are involved in reward, allowing the use of selective serotonin reuptake inhibitors (SSRIs) to alleviate feelings of anxiety and dysphoria, he continued.

Prior research had shown that people who are behaviorally disinhibited frequently have a lower turnover of serotonin. “But there has been inadequate attention paid to the common pathway of neurobiologic changes that occur once a person becomes an alcoholic,” Dr. Goldman said. “There are many different reasons that a person might initially become an alcoholic. For example, they might drink because they are impulsive, because they are anxious, etc ... but once they have begun, there is a common neurobiology experienced by all people who become addicted.” These changes are induced in the brain regardless of the preexisting vulnerability, and the research shows a common pattern of neurobiologic change.

An early deficit of serotonin may result from genetic factors, as well as social stress, which can render subjects more tense, anxious, and potentially aggressive. These subjects tend to drink more alcohol—most likely to calm down—and they have less negative effects from alcohol intake, it was observed. These “low responders” are most likely to develop alcoholism. Long-lasting alcohol intake may further disturb the serotonergic system and induce clinical depression, thus increasing the long-term relapse risk.

IS BIOLOGY DESTINY?

“What one is really doing in focusing on a particular neurotransmitter is slightly artificial because there are no neurotransmitters that are actually acting outside the context of a neuronal circuit. But on the other hand, the biosynthetic and receptor genes for serotonin are crucial for circuits of behavior control and reward. So, by studying that neurotransmitter and the genes that modulate its function, one is getting a good entry point into that biology,” explained Dr. Goldman.

The research, designed to relate the functional serotonin transporter polymorphism to in vivo functional biology, revealed that “it was more powerful to relate the functional gene variant to functional biology in the brain to the study of controls rather than [to] the study of alcoholics or clinical populations,” said Dr. Goldman. A significant relationship was found in brain serotonin transporter density in the controls. But surprisingly, noted Dr. Goldman, “In the alcoholics, in whom there is a longstanding change in serotonin function due to the effects of alcohol on that system, the effects of the genotype on the brain phenotype are obscured.” It seems that although genes may affect the intermediate phenotypes in the brain and thereby ultimately alter vulnerability, once a person has entered into alcohol addiction there may be a modification of the neurochemistry as the drug destroys the interindividual differences that were a result of inherited genetic variance. “We have a situation in which people start off differentially vulnerable to drugs and alcohol due to inherited genetic variance, but once you enter into a career of alcohol or other substance abuse, then there are long-standing changes that can serve to mask other changes,” said Dr. Goldman.

“It came as a surprise to me that the more extreme clinical population may actually be a less useful population in which to explore the effects of genotype on biology. My prejudice would have been that it would have been a good strategy to use the more extreme clinical population—alcoholics or early onset alcoholics—to look for the effects of genes on behavior, but on the other hand, you realize an alcoholic has exposed his brain to a drug that exerts many effects and some of those effects are vital in the addictive process.” The researchers realized that the better populations for gene brain function correlations are populations that haven’t undergone excessive exposure.

THE LONG AND SHORT OF IT

Of the two forms of the promoter serotonin transporter polymorphism, the long and the short allele, the shorter allele is responsible for a lower density of serotonin transporters in the brain and in vitro; it is also responsible for lower rates of transcription of the gene. “So, one might have thought the long allele is associated with a higher density and the a priori hypothesis might have been that the lower transcriber allele would be associated with reduced anxiety. That would be analogous to giving the person fluoxetine, which blocks the serotonin transporters and alleviates anxiety,” explained Dr. Goldman. But a number of studies revealed that the short allele, which is associated with lower transcription and lower transporter density, is also associated with high rates of anxiety and dysphoria.

“The actual association between gene and behavior was found, but in the opposite direction of what might have been predicted based on the known pharmacology of the SSRI drugs and their effects on behavior and mood,” said Dr. Goldman. “That was a surprise to anyone thinking in simplistic terms about the effect of a genetic variance in transporter function on behavior. When you realize that you have such a gene variant and might have long-lasting adaptive changes, you can easily propose a mechanism by which the paradoxical association of opposite-allele-to-behavior could be observed.

“Scientists like it when other scientists are perplexed, and it’s usually in the contradiction that the most interesting stories lie. The fact of the matter is that we don’t know why it should be that the lower transcribing allele should make a human who’s more anxious,” Dr. Goldman reflected. “It’s so bizarre that no one would have believed it otherwise.”

NR