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A Neurogenetic Approach to Alcoholism

May 1, 2001
Heinz, A., Mann, K., Weinberger, D.R., & Goldman, D. Heinz, A., Mann, K., Weinberger, D.R., & Goldman, D
Heinz, A., Mann, K., Weinberger, D.R., & Goldman, D. (2001, April). Serotonergic dysfunction, negative mood states, and the response to alcohol. Alcoholism: Clinical and Experimental Research, 25(4), 487-495.
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  • Researchers are integrating the fields of genetics and neurobiology to better understand the development of alcoholism
  • The neurotransmitter serotonin is an important modulator or inhibitor of certain behaviors
  • Three behavior patterns - disinhibition, negative mood states, and a low response to alcohol - are relevant to the development of alcoholism
  • Both pre-existing and alcohol-induced differences influence serotonergic neurotransmission

Scientists are moving beyond the knowledge that alcoholism is a disease. They are now integrating the previously disparate research fields of genetics and neurobiology to investigate how genetic influences may alter the function of neurotransmitters prior to and during the development of alcoholism. More specifically, a review in the April issue of Alcoholism: Clinical & Experimental Research examines the link 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.

"Several hypotheses have tried to explain the association between serotonergic dysfunction and alcoholism," noted Andreas Heinz, associate professor of addiction research at the University of Heidelberg and lead author of the paper. "Sometimes, these hypotheses seemed to be contradictory. For example, it was not easy to understand why serotonergic dysfunction should be associated with depression and aggression, or what the impact of disposition versus the consequences of long-term alcohol intake might have on the serotonergic system."

In this review, the neurochemical serotonin is the key player. Serotonin is an important modulator within what is called the behavior inhibition system. The neurotransmitter is very likely influenced by genetics, early stress experiences, as well as alcohol itself. 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 authors believe that three behaviors or "mechanisms" in particular - disinhibition, negative mood states such as anxiety and depression, and a low response to alcohol - may explain the relationship between serotonin and alcoholism. They reviewed a number of primate and human studies to form an integrated perspective on serotonin and its role in the development of alcoholism.

David Goldman, chief of the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism, said that one of the key strengths of this approach to understanding alcoholism is its inclusive nature. "This article includes both the genetic influences, where there’s a biological substrate or tendencies inherent to the person, and also the secondary changes that alcohol induces in the function of this neurotransmitter system. Furthermore, it looks at the possible consequences of both the inherited differences and the secondary changes that effect behavior and vulnerability to alcoholism."

Goldman noted that 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 neurobiological changes that occur once a person becomes an alcoholic," he 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 what the pre-existing vulnerability was, and this review showed a common pattern of neurobiological change, at least as far as serotonin is concerned."

"Serotonin seems to play two roles," said Heinz. "One, an early deficit 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." Having fewer negative effects from drinking alcohol means the same thing as having a low response to alcohol; these are people who can ‘drink like a fish’ without getting drunk. Sons of alcoholics, for example, are often ‘low responders’ and most likely to develop alcoholism themselves. "Two," continued Heinz, "long-lasting alcohol intake may further disturb the serotonergic system and induce clinical depression, thus increasing the long-term relapse risk. A genetically defined subgroup of alcoholics may be specifically vulnerable to these effects."

Heinz spoke of two kinds of studies, primate and human, that demonstrated the relationship between serotonergic dysfunction and alcohol use and/or abuse.

"If non-human primates have to grow up without their mothers," he said, "they show a long-lasting reduction in serotonergic neurotransmission. When young, they are anxious, socially incompetent and seem to feel threatened - which are all negative mood states. As adult male individuals, they still show signs of serotonergic dysfunction, as well as two important predictors of subsequent alcohol intake, impulsive aggressiveness and increased tolerance to the side effects of alcohol intake." Heinz said the animals acted more aggressively because they were, in fact, more socially incompetent and felt threatened by social interactions. He speculated that the primates liked the sedative effects of alcohol because it reduced their feelings of anxiety. Indeed, the stronger their serotonergic dysfunction, the more alcohol they tolerated. There were comparable clinical findings in the human adoption studies examined.

"Early social stress that was related to late placement in adoptive families," said Heinz, "was also associated with extensive alcohol intake. We found that psychotherapeutic approaches often emphasized the importance of insecure mother-child bonding and social stress in the development of alcoholism. The reviewed studies and our studies show that such early social stress indeed has long-term effects on brain serotonergic function. These individuals may consume more alcohol because they feel less sedative alcohol effects - since they are rather tense, aroused or anxious - and thus need more alcohol to compensate for their arousal."

Additional studies of human alcoholics have found that long-term alcohol intake seems to further disturb serotonergic neurotransmission. "A reduction in the serotonin transporter," said Heinz, "which recycles serotonin after it has been released from the nerve terminals, was correlated with clinical depression. This is, in turn, a predictor of an increased relapse risk when patients are followed for several years. In other words, the genetic constitution of the serotonin transporter may render some subjects more vulnerable to the neurotoxic effects of alcohol intake."

"We are beginning to understand through neurobiology and genetics," noted Goldman, "what some of the clinical subgroups of alcoholism and psychiatric diseases are. These subgroups are going to have different vulnerabilities and also different treatment responses."

"This review shows that social stress factors," said Heinz, "especially early social separation, have long-term effects on the brain and on neurotransmitter systems that affect social behavior and the response to alcohol. There are also negative long-term consequences of alcohol intake, such as a loss of serotonin transporters, that may affect mood states. We need to further examine the association between stress hormone activation, both during early separation stress and detoxification, and serotonergic dysfunction. We also need to clarify the relationship between genetic disposition and an increased vulnerability of the serotonergic system to chronic alcohol intake."