Previous research has shown that alcoholism can cause damage to certain brain regions, including reduced metabolism, blood flow and tissue volume, as well as a reduced density of neurons and glial cells. A new study of neurons and glial cells in the orbitofrontal cortex (ORB), a prefrontal region of the brain that is heavily involved in decision-making processes and emotional and motivational behavior, has found that both the presence and duration of alcoholism may cause a decrease in the overall density of neurons in the ORB.

Results are published in the November issue of Alcoholism: Clinical & Experimental Research.

"Both human and animal research has shown that lesions or malfunction of the ORB result in various degrees of inability to use past experiences to guide future actions or to adapt responses to the environment when there are changes to the stimuli in that environment," said Jose Javier Miguel-Hidalgo, assistant professor of psychiatry and human behavior at the University of Mississippi Medical Center and corresponding author for the study. "Some human neuroimaging studies have also found that the value of rewards, the expectations about them, and their pleasantness are linked to the ORB."

"The interplay of neurons and glia has emerged as an important issue in understanding brain function, psychiatric disease, and addiction," added John H. Krystal, director of the National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism at Yale University School of Medicine. "Glia, once thought to 'merely' provide support to neuronal function, are now known to respond to metabolic changes and neurotransmitters released by neurons and, in turn, to provide key substrates for neuronal metabolism and to release substances that modulate neuronal activity and neurotrophic factors."

Researchers used a three-dimensional cell-counting method in postmortem brain tissue to examine the packing density of neurons and glial cells in the ORB (Brodmann's area 47) among 23 subjects: 15 who met clinical criteria for alcoholism (8 had committed suicide, 7 had not); and eight normal comparison subjects.

"In the ORB of alcoholics we found a progressive loss of neurons that is more pronounced the longer the period of alcohol abuse," said Miguel-Hidalgo. "This means that continued abuse of alcohol does not just interfere with the powers of decision and self-control when someone is intoxicated, but results in a progressive and very likely irreversible loss of neurons in an area of the brain that is directly involved with an ability to adapt to new situations. This also suggests that it is never too late to stop abusing alcohol."

Researchers also found a reduced density of glial cells among the alcoholics that appeared early in the course of alcoholism, but this did not appear to be correlated with the duration of alcohol abuse. "Since glial cells are critically necessary to support the function and survival of neurons," said Miguel-Hidalgo, "the glial deficit may be an important factor in the progressive loss of neurons."

In fact, noted Krystal, the resulting "mismatch" or changes in the density ratio of glia and neurons across several cortical layers may themselves be illuminating. "These findings suggest that disturbances in the interplay of neurons and glia in the ORB that arise as a consequence of the toxic effects of alcoholism may lead to features known to be associated with alcoholism," he said. "That is, the tendency to display impulsive behavior, risky or maladaptive decision making, and compulsive reward-seeking behavior."

"The fact that there was no difference between suicides and non-suicides in the neurons or glial cells of the ORB means that the acute effects of alcohol might be more important in increasing the probability of suicide than longer-lasting changes in numbers of glial cells or neurons," said Miguel-Hidalgo. "Further, since the probability of suicide is high among alcohol abusers, it remains crucial to find ways to curtail excessive and prolonged alcohol intake." His research will continue, with a focus on how molecular changes in neurons are correlated with molecular changes in glial cells, and if glial deficiencies might construe a vulnerability factor even before subjects become alcoholics.

"It would be very interesting to know whether these glial deficits contribute to the neuronal dysfunction that contributes to risky behaviors," mused Krystal, adding that many aspects of this study warrant future research. "What about the interplay of vulnerability to depression, the impact of early life stress, and exposure to alcohol? To what extent do the findings of this study reflect the impact of major depression upon the risk for alcohol dependence? Who is particularly likely to have glial and neuronal loss? And last but certainly not least, we want to know about the interplay of particular genotypes and early childhood maltreatment or later psychological traumatization with respect to these same genotypes."

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Reduced Glial and Neuronal Packing Density in the Orbitofrontal Cortex in Alcohol Dependence and its Relationship to Suicide and Duration of Alcohol Dependence," were: James C. Overholser of the Department of Psychology at Case Western Reserve University; Herbert Y. Meltzer of the Department of Psychiatry at Vanderbilt University; Craig A. Stockmeier of the Department of Psychiatry and Human Behavior at the University of Mississippi Medical Center, as well as the Department of Psychiatry at Case Western Reserve University; and Grazyna Rajkowska of the Department of Psychiatry and Human Behavior at the University of Mississippi Medical Center. The study was funded by the National Institute of Mental Health, the National Center for Research Resources, and the Alcohol Beverage Medical Research Foundation.