COLUMBUS, Ohio – Scientists have learned how a geneticvariation long suspected in making some people susceptible toalcoholism 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'sthe difference in protein expression that may make receptors on certainbrain cells much more vulnerable to the effects of addictive drugs,said Wolfgang Sadee, the study's lead author, professor and chair ofpharmacology and director of the pharmacogenomics program at Ohio StateUniversity. These particular receptors, called mu opioid receptors,serve as a molecular docking station for narcotic drugs and alcohol.
Untilnow it wasn't clear exactly what about this genetic variation, calledA118G, would increase a person's chances of developing a drugaddiction. (A118G is a variation in what researchers call the mu opioidreceptor gene.)
While Sadee and his team didn't look at theinteraction between narcotics and the mu opioid receptor, they suspectthat differences in protein production may leave brain cells with thesereceptors more open to the effects of drugs.
“The realsignificance of this work is that one day, we may be able to tailortreatments for addiction based on how a person's genes behave,” saidSadee, who is also chair of pharmacology at Ohio State .
The study appears in the current issue of the Journal of Biological Chemistry.
Theresearchers studied brain tissue samples taken from the cerebral cortexand the pons of human cadavers. The pons is a cluster of nerve fiberson the front of the brainstem, and it's responsible for relayingsensory messages from the spinal cord to the cerebellum. The cerebralcortex is a thin layer of tissue that covers the surface of thecerebral hemisphere; it is responsible for processes such as thought,memory, motor function and social abilities.
The researchersstudied these particular brain tissues because both are rich in cellsthat have mu opioid receptors. Opioids are pain-relieving medicationsor illegal drugs that can be quite addictive, and these receptors inbrain cells serve as a target for narcotic drugs. The interactionbetween narcotics and the receptors stops a person from feeling painand also triggers the sensations of craving, reward and expectationthat addicts often experience.
The researchers extracted andanalyzed DNA and RNA from the brain tissues. They then injected thegenetic material into ovary cells from Chinese hamsters. They couldthen measure the changes in the regulation and processing of messengerRNA (mRNA). mRNA carries instructions from the DNA inside a cell'snucleus to the rest of the cell, telling the cell that it's time tomake more protein.
Surprisingly, the mu opioid receptor genesthat carried the A118G variation (such variations in genes are calledsingle-nucleotide polymorphisms) produced less mRNA than did the geneswithout the variant. In addition, the A118G change caused a ten-folddecrease in protein production inside the hamster ovary cells.
Themu opioid receptor gene is the first of 20 or so genes implicated indrug addiction that Sadee and his colleagues want to study. Those othergenes may play a role in addiction to various drugs, including alcoholand nicotine.
“Drug addiction is a complex disorder, one that hasa strong genetic component,” Sadee said. “It's very hard to prove thatthere is a causative link between one polymorphism and addiction. Butthe 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.
The work was supported by a grant from the National Institutes of Health.
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