Gene Variant Suggests Link To Addiction Vulnerability

Because the μ-opioid receptor (OPRM1) is a primary docking station for opioid drugs, polymorphisms in the gene encoding OPRM1 are thought to be causative agents for a susceptibility to narcotic drug dependence. One variant in particular, the single nucleotide polymorphism A118G, has been associated with a vulnerability to addiction to heroin, nicotine, and alcohol. Also, A118G has been shown to affect a response to naltrexone therapy. But numerous studies have been unsuccessful in attempting to show how the A118G variant increases someone's chances of developing a drug addiction.

Now researchers at Ohio State University have found that A118G causes a change in the expression of OPRM1 protein levels. It is the difference in protein expression that may make receptors on certain brain cells much more vulnerable to the effects of addictive drugs. In laboratory studies, this variation greatly reduced the amount of protein that the DNA produced in a cell.

“It's very hard to prove that there is a causative link between one polymorphism and addiction, but the current study provides strong evidence that there is,” lead author Wolfgang Sadee, M.D., Ph.D., told Psychiatric News.

Sadee is the Felts Mercer Professor of Medicine and Pharmacology, chair of the Department of Pharmacology, and director of the Program in Pharmacogenomics at Ohio State University's College of Medicine and Public Health. The study was published in the September 23 Journal of Biological Chemistry.

The researchers extracted and analyzed DNA and RNA from samples of human cadaver brain tissue taken from the cerebral cortex and the pons, areas both rich in cells that have μ-opioid receptors. They found that the μ-opioid receptor gene that carried the A118G variation produced less messenger RNA (mRNA) than did the common gene variant. When they injected the cloned genetic material into the ovary cells of Chinese hamsters and measured changes in the regulation and processing of mRNA, they again found reduced mRNA and very low protein levels with the A118G variant.

Sadee said the finding that the A118G transition makes much less mRNA in the cell indicates that differences in protein production (this still needs to be confirmed in vivo) may leave brain cells with these receptors more open to the effects of alcohol and other drugs.

“This is a bit puzzling as one would have expected less association with addiction in the A118G carriers since there is loss of function. Previous work was based on the assumption that the A118G enhances affinity to beta-endorphin, or a gain of function, and therefore maybe enhances the hedonic effects of endorphins. Unfortunately the enhanced beta-endorphin affinity study could not be reproduced, and yet clinical studies continue to refer to it,” he said.

“Those who carry the 118G allele would therefore be expected to have lower OPRM receptor levels. Most are heterozygous, and there are much fewer homozygous 118G carriers where we would expect greater effects,” he said.

Sadee said their study shows a definitive functional change—an important step in linking to clinical association studies. “How the functional change translates into a clinical phenotype is the next important question—and may shed light on this aspect of susceptibility to addiction. There are no clear-cut answers if one wishes to go from a molecular mechanism to a complex downstream response,” he said.

“The real significance of this work is that one day we may be able to tailor treatments for addiction based on how a person's genes behave,” he said.

Commenting on the Sadee report, Jon-Kar Zubieta, M.D., Ph.D., an associate professor of psychiatry and radiology and an associate research professor in the Molecular and Behavioral Neuroscience Institute at the University of Michigan, told Psychiatric News, “Many of the addictive drugs have effects, both direct and indirect, on the opioid system and μ-opioid receptors. Depending on the location in the brain, these receptors can be involved in a number of different processes—from pain control to responses to salient stimuli, such as pain, or even pleasurable experiences.”

The work was supported by a grant from the National Institute on Drug Abuse.

An abstract of “Allelic Expression Imbalance of Human mu-Opioid Receptor (OPRM1) Caused by Variant A118G” is posted at<www.jbc.org/cgi/content/abstract/280/38/32618?>.▪

J. Biol. Chem. 2005 280 32618