Alcohol's Effects On Gene Expression In The Central Nervous System

"All of our cells have exactly the same deoxyribonucleic acid (DNA), which means they all have the same genes," explained William J. McBride, symposium organizer and professor of neurobiology at the Indiana University School of Medicine. "The reason that different cells can appear and work so differently with the same genes – giving us, for example, unique eyes, skin, or hair – is that only some genes are used or 'turned on' in each cell. This is called gene expression."

McBride said that researchers now know that alcohol can change gene expression in the brain, and that these changes are likely responsible for many of the 'symptoms' of addiction, such as tolerance, physical dependence, and craving, as well as the 'consequences' of alcoholism, such as brain damage.

"The challenge has been to find out which genes – out of more than 50,000 – are turned on or off in the brains of alcoholics," he said. "Microarray studies – the examination of a small glass microscope slide that has thousands of different DNA samples attached to it – that are applied to brain function are just beginning in the field of alcoholism. Several years ago, it was impossible to analyze more than a handful of these genes, however, microarray technology has changed that."

Symposium speakers at the June 2004 Research Society on Alcoholism meeting in Vancouver, B.C. presented the following findings from recent studies that used genetic animal models:

# Gene expression profiling in the nucleus accumbens, prefrontal cortex, and ventral tegmental areas show that distinct biological pathways are associated with alcohol's action in specific brain regions and certain mouse strains.

"We were able to use gene expression profiling to determine that alcohol produces multiple effects on different biological processes," said McBride, "and that these changes are different in several brain regions which may be involved in alcohol addiction."

# Researchers have identified individual genes and gene networks that may play an important role in determining the behavioral responses to alcohol as well as possibly influencing drinking behavior.

"Thus far, genes that appear to be responsive to alcohol include genes involved in the intracellular signaling process (which can alter how the neuron functions), neuropeptide signaling (which modulates nerve cell activity), and myelin structure (which is needed for communication between nerve cells)," said McBride. "Gene expression profiling has also been used to identify chromosomes and chromosomal regions that influence alcohol drinking and response to alcohol."

# Intracranial self-administration of ethanol into the posterior ventral tegmental area (VTA) of alcohol-preferring rats produced results suggesting that the reinforcing effects of alcohol are activating VTA dopamine neurons and producing changes in synaptic connections that resemble those that occur in memory and learning.

"Learning and memory require enhanced synaptic function between neurons," explained McBride. "Enhanced synaptic function is characterized by increased formation of synaptic proteins. The stimulation of VTA dopamine neurons by alcohol increases the expression of genes involved in the synthesis of synaptic proteins in target regions of the VTA. In short, these results suggest that alcohol can produce changes in the brain reward system that can further increase the rewarding effects of alcohol."

# Microarray techniques confirmed earlier reports indicating that chronic alcohol exposure/withdrawal differentially alters gene expression in the prefrontal cortex of mice. More than 300 genes were found to be altered by acute alcohol treatment.

"The prefrontal cortex is involved in motivated behaviors," noted McBride. "Studies with humans indicate that this brain region is sensitive to the effects of heavy alcohol drinking and repeated withdrawals. The microarray technique provides insight into cellular changes that occur over time with chronic alcohol drinking and repeated withdrawals."

Collectively speaking, added McBride, findings presented at the symposium demonstrate the quantitative and qualitative applications of microarrays to studying the genetic and biological bases of alcoholism and alcohol abuse within discrete brain regions.

"For researchers, microarray technology has the potential of studying the genetic and biological bases of alcohol's rewarding effects, sensitivity to the effects of alcohol, development of tolerance to the effects of alcohol, development of alcohol dependence, and alcohol withdrawal severity," he said. "For the average reader, knowing which genetic profiles might contribute to excessive alcohol drinking could be used to identify risk factors that contribute to alcoholism and alcohol abuse, and could aid in the development of selective treatment strategies for different subgroups of alcoholics."

McBride added that, despite recent advances, researchers need further developments in microarray technologies and bioinformatic approaches to better understand the complex neurobiological mechanisms underlying alcohol addiction. "Future research will need to determine changes in gene expression in very discrete neuronal pathways that may be involved in mediating the effects of alcohol that lead to addiction," he said. "Future studies will also require the integrative efforts of many investigators working with different animal models in order to identify the multiple genetic factors that contribute to the risk for alcoholism and alcohol abuse."

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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/presenters of the symposium proceedings published in the ACER paper, "Alcohol Effects on CNS Gene Expression on Genetic Animal Models," were: Zachary A. Rodd, Wendy N. Strother and Howard J. Edenberg of the Indiana University School of Medicine; Robnet T. Kerns and Michael F. Miles of the Virginia Commonwealth University; and Joel G. Hashimoto and Kristine M. Wiren of the Oregon Health & Science University. Symposium research was funded by the National Institutes of Health, and the Indiana Genomics Initiative of Indiana University, which is supported in part by Lilly Endowment Inc.