An unanswered question in alcoholism research has been what drives the transition from moderate alcohol consumption to alcohol dependence. Researchers at The University of Texas at Austin set out to discover if a molecule that regulates gene expression in the brain called Lim-only 4 (Lmo4) could facilitate this transition. In doing so, they discovered a molecular mechanism in the brain that is critical to the development of alcoholism, providing potential new targets for treatment.
"Progress on (alcoholism) treatment has been hindered by the complexity of the effects alcohol has on the brain," said Rajani Maiya, a research scientist in the laboratory of Dr. Robert Messing in the Department of Neuroscience and the Waggoner Center for Alcohol and Addiction Research. "Our in-depth analysis of how the brain responds to alcohol revealed two potential molecular targets for intervention: the kappa opioid receptor and the extracellular matrix. We show that blocking the function of these two targets reduced alcohol consumption and thus we believe drugs or treatments that inhibit the function of these targets will be beneficial for alcoholics around the world."
Maiya is lead author of the paper, which was published in March in Molecular Psychiatry.
Maiya and the team used a mouse model to zero in on the transcription co-factor LMO4. Transcription factors facilitate the process of transcription, the process by which DNA is converted to RNA.LMO4 belongs to a unique class of these transcription factors that do not interact with DNA directly, but instead interact with a number of other transcription factors inside brain cells, working to turn genes on and off. LMO4 is a transcription factor known to regulate about 1,000 genes and acts like the conductor of an orchestra, signaling some genes to express, while commanding others to be silent.
Researchers discovered that when they limited LMO4 in a particular brain region known to be important in alcoholism, the basolateral amygdala, alcohol consumption decreased.
"This helps us understand one way that moderate drinkers become dependent on alcohol," said Maiya.
To determine how LMO4 decreases alcohol consumption, Maiya and her colleagues decided to look closely at genes whose expression was altered when LMO4 expression was reduced. Of the 1,000 genes whose expression was altered, the scientists found two targets that were compelling; the kappa opioid receptor and a group of genes that are related to the extracellular matrix. Scientists have known for some time that the kappa opioid receptor, a signaling receptor in the brain, is a regulator of alcohol consumption. The team of researchers discovered that LMO4 directly regulates the kappa opioid receptor by binding to parts of the receptor. When researchers limited the expression of LMO4, alcohol consumption decreased even when they added a drug that was designed to activate the kappa opioid receptor and increase alcohol consumption.These results provide evidence that LMO4 and Kappa opioid receptors are part of the same pathway that regulate alcohol consumption.
The other identified molecular target, the extracellular matrix (ECM), is the structure that surrounds all cells in the brain. When Maiya and colleagues disrupted this structure in the basolateral amygdala by injecting an enzyme that degrades it, they found that mice consumed less alcohol. This suggests that treatments that interfere with ECM function could be useful to treat alcohol use disorders.
Next, the team will look at how alcohol consumption affects the expression of genes regulated by LMO4 in the brain. Dr. Maiya hopes that this will provide a transcriptional signature of decreased drinking in the brain. Such signatures can be used to screen for candidate drug molecules that can mimic this signature and consequently reduce alcohol consumption.
Matthew B. Pomrenze , Thi Tran, Gayatri R. Tiwari, Andrea Beckham, Madison T. Paul, R. Dayne Mayfield and Robert O. Messing of the University of Texas also contributed to the research. The research was supported by the National Institutes of Health.
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