Possibility of tailored treatments for addiction based on how a person's genes behave

Scientists have learned how a genetic variation long suspected in making some people susceptible to alcoholism and narcotic drug addiction actually does so.

In laboratory studies, this variation greatly reduced the amount of protein that the DNA in a cell produced.

It's the difference in protein expression that may make receptors on certain brain cells much more vulnerable to the effects of addictive drugs, said Wolfgang Sadee, the study's lead author, professor and chair of pharmacology and director of the pharmacogenomics program at Ohio State University. These particular receptors, called mu opioid receptors, serve as a molecular docking station for narcotic drugs and alcohol.

Until now it wasn't clear exactly what about this genetic variation, called A118G, would increase a person's chances of developing a drug addiction. (A118G is a variation in what researchers call the mu opioid receptor gene.)

While Sadee and his team didn't look at the interaction between narcotics and the mu opioid receptor, they suspect that differences in protein production may leave brain cells with these receptors more open to the effects of drugs.

"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," said Sadee, who is also chair of pharmacology at Ohio State .

The study appears in the current issue of the Journal of Biological Chemistry.

The researchers studied brain tissue samples taken from the cerebral cortex and the pons of human cadavers. The pons is a cluster of nerve fibers on the front of the brainstem, and it's responsible for relaying sensory messages from the spinal cord to the cerebellum. The cerebral cortex is a thin layer of tissue that covers the surface of the cerebral hemisphere; it is responsible for processes such as thought, memory, motor function and social abilities.

The researchers studied these particular brain tissues because both are rich in cells that have mu opioid receptors. Opioids are pain-relieving medications or illegal drugs that can be quite addictive, and these receptors in brain cells serve as a target for narcotic drugs. The interaction between narcotics and the receptors stops a person from feeling pain and also triggers the sensations of craving, reward and expectation that addicts often experience.

The researchers extracted and analyzed DNA and RNA from the brain tissues. They then injected the genetic material into ovary cells from Chinese hamsters. They could then measure the changes in the regulation and processing of messenger RNA (mRNA). mRNA carries instructions from the DNA inside a cell's nucleus to the rest of the cell, telling the cell that it's time to make more protein.

Surprisingly, the mu opioid receptor genes that carried the A118G variation (such variations in genes are called single-nucleotide polymorphisms) produced less mRNA than did the genes without the variant. In addition, the A118G change caused a ten-fold decrease in protein production inside the hamster ovary cells.

The mu opioid receptor gene is the first of 20 or so genes implicated in drug addiction that Sadee and his colleagues want to study. Those other genes may play a role in addiction to various drugs, including alcohol and nicotine.

"Drug addiction is a complex disorder, one that has a strong genetic component," Sadee said. "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."

Sadee conducted the study with Ohio State colleagues Ying Zhang, Danxin Wang, Andrew Johnson and Audrey Papp.