A central issue in alcoholism research is determining the biological differences of those individuals who have a genetic vulnerability to alcoholism. This vulnerability may lead some individuals to abuse alcohol (and eventually lose the ability to control their alcohol consumption). In the March issue of Alcoholism: Clinical & Experimental Research, researchers examine a group of young people who are at increased genetic risk for alcoholism as a result of having a high prevalence of alcoholism in their biological lineage. Study authors hypothesize that high risk for alcoholism is related to brain hyperexcitability, including impaired brain inhibitory mechanisms.
"We have been studying brain deficits in chronic alcoholics for many years using brain wave recordings," said Bernice Porjesz, associate professor of psychiatry at State University of New York, Health Science Center and one of the paper’s authors. "We have found that some of these deficits do not recover with prolonged abstinence from alcohol. Our studies of high-risk children of alcoholics, prior to any exposure to alcohol, indicate that many of these electrophysiological anomalies antecede the development of alcoholism. Based on these studies, we hypothesized that a predisposition to developing alcoholism involves a deficit in central nervous system inhibition, which can also be called hyperexcitability."
Porjesz explained that most of the excitatory neurotransmission in the human brain is likely mediated by glutamate or a related excitatory amino acid. One category of glutamate receptor, N-methyl-D-aspartate (NMDA), is also responsible for some of the diverse effects of alcohol on the central nervous system (CNS). Gamma- aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the human brain. GABAA receptors are also sensitive to alcohol and have been found to be deficient in the brains of alcoholics. A balance between these excitatory (glutamatergic) and inhibitory (GABAergic) systems in the brain provides CNS homeostasis, which is important for stable affective and cognitive processing (such as learning and memory function).
"Normal brain function requires a balance between inhibitory (such as GABA-mediated) and excitatory (such as NMDA-mediated) neural systems," said George Fein, president of and senior scientist at Neurobehavioral Research, Inc. "The phenomenon [Dr. Begleiter and his colleagues] chose to study is called ‘mismatch negativity,’ a brain wave that reflects the brain’s detection of changes in the ongoing stream of sounds in the environment. Mismatch negativity occurs ‘out of consciousness,’ in this case it was recorded while the subjects were reading."
Researchers used scalp electrodes to record brain electrical activity of two groups, one considered high risk and another considered low risk for developing alcoholism. Event-related potentials (ERPs) are brain responses that manifest as small voltage changes that can be measured in microvolts. ERPs consist of positive and negative waves that are linked in time to specific sensory or cognitive events, and are extremely sensitive within a fraction of a second to ongoing processing in the brain. Mismatch negativity (MMN) is an ERP component that occurs when a series of repetitive standard stimuli (such as tones of a certain frequency and/or intensity) is interrupted by a deviant tone (such as one that is louder or of a different frequency from the standard). It is not necessary for the subject to attend to these stimuli. MMN can be elicited even while the subject is reading (as in this experiment), indicating that it indexes a (largely) automatic component of the brain’s working memory system. MMN reflects the involuntary matching of incoming stimuli with the current template in short-term acoustic memory. The more deviant the incoming stimulus from the standard, the larger the MMN.
"Mismatch negativity can be taken as an index of auditory memory function," said Porjesz, "and can be used as a tool to investigate underlying neurochemical mechanisms. Researchers have long known that NMDA is involved in long-term memory, but recent work with mismatch negativity indicates that NMDA is also involved in cortical working memory. Deficits in mismatch negativity generation may be associated with impaired neurotransmission at NMDA glutamate receptors. Conversely, NMDA antagonists have been found to inhibit mismatch negativity, suggesting that glutamate is the primary neurotransmitter involved in mediating the mismatch negativity. Therefore, individuals characterized by an enhanced mismatch negativity may actually have an excess of glutamate in the CNS. This increased concentration of glutamate may underlie increased levels of excitability in behavioral as well as electrophysiological measures. Furthermore, chemical transmission by the nervous system makes the process vulnerable to interference or inhibition by drugs."
"There has been speculation that the balance between GABA and NMDA affects the mismatch negativity," added Fein, "and there have been studies showing that blocking NMDA receptors abolishes the intracortically recorded correlate of the mismatch negativity. This study shows that mismatch negativity is larger in individuals at increased genetic risk for alcoholism, thereby providing direct evidence for increased brain excitability in these individuals. [In other words,] brain hyperexcitability results in an increased magnitude of the mismatch negativity, meaning the brain is more responsive (or excited) by changes in the environment. These findings provide fertile ground for speculation that GABAergic and NMDA neural system differences in such individuals may underlie this brain hyperexcitability, and may be implicated in the brain hyperexcitability associated with the genetic vulnerability to alcoholism."
"Individuals manifesting this deficit in inhibition (or hyperexcitability) on the electrophysiological level are also more likely to manifest behavioral disinhibition," said Porjesz. "Both high risk and alcoholic individuals have been characterized as having a disinhibited personality. Behaviorally, this has been manifested as a higher incidence of risk taking behavior, such as drug and alcohol abuse, smoking, risky sexual activity, aggression and antisocial behavior."
Both Porjesz and Fein observed that the excessive neural excitation reflected by increased MMN in the high-risk sample may lead these individuals to use alcohol for self-medication purposes, such as reducing their neural excitation to more normal values. Fein said that other studies have shown that alcohol consumption reduces MMN in a dose-related fashion.
"For these individuals," said Porjesz, "their first exposure to alcohol provides an immediate ‘normalizing’ effect. However, this effect is temporary and requires larger and larger amounts of alcohol to achieve an effect. This is referred to as tolerance."
Fein said the study’s results are exciting for additional reasons. "First, they occur in the absence of alcohol," he said. "It’s easy to find that alcohol use or abuse affects the body and brain. Effects associated with the predisposition to alcoholism are much harder to find. Second, the finding of an increase in mismatch negativity makes the study of greater interest. Things that are not good to have - such as schizophrenia, attention deficit disorder, alcoholism, or a genetic vulnerability to schizophrenia - are often associated with negative abnormalities. Such individuals often have impaired memory, attention, etc. A finding that something is less in such individuals is not that exciting because many, many mechanisms could contribute to such a finding in human studies. The subject could be less attentive, less motivated, etc. A result that something is bigger or increased makes the finding more clear-cut in that a direct mechanism underlying the phenomenon under study is affected, rather than some general difference that makes most everything a little worse."