Why these rats got hooked and stayed hooked on cocaine

Researchers looked in rats' brains for the genetic instructions needed to make a key pleasure receptor, called D2, that allows brain cells to receive signals sent by cocaine. (Credit: iStockphoto)

An animal study can’t explain all the factors that contribute to differences in addiction among people. But a new study of rats addicted to cocaine could help clarify the roles played by both inherited traits and addiction-related changes in the brain.

The researchers looked in rats’ brains for the genetic instructions needed to make a key pleasure receptor, called D2, that allows brain cells to receive signals sent by cocaine. They found that more addiction-prone rats had lower levels of D2 instructions to begin with, compared with other rats, in an area of the brain known to play a major role in addiction.

The addiction-prone rats also were more likely to carry a specific mark on their DNA called an epigenetic tag. This tag, called H3K9me3, kept their brain cells from reading the gene for D2 receptors.

But after they became hooked on cocaine, the addiction-prone rats had the same levels of D2 as the less addiction-prone ones. And when the cocaine was taken away for a while, these rats were more likely to relapse to addictive behavior if they had started out with the epigenetic tag that kept their cells from reading the D2 gene.

[Mice resist cocaine if they have stuff to do]

Meanwhile, a comparison group of rats didn’t show signs of addiction, and didn’t relapse following abstinence.

The scientists found that these “addiction-resilient” rats started out with lower levels of instructions for making a different brain molecule also known to play a role in addiction, called FGF2. They were also more likely to carry an epigenetic mark that kept them from reading the FGF2 gene. And this might have helped protect them from becoming addicted.

“Because we had access to these rats that were bred for certain traits, and were able to control for environmental factors, such as the amount of drug exposure, we could assess differences in the brain both before and after the rats became addicted,” says Shelly Flagel, lead author of the new study and an assistant professor of psychiatry at the University of Michigan. “By studying their gene expression and epigenetics, as well as their response to drug availability and drug-related cues, we can link these differences in the brain to addiction-like behaviors, such as relapse.”

And that kind of understanding could be a model to help the broader understanding of addiction in humans as well, Flagel says.

The more that addiction is seen as having biological roots and origins in genetic traits that are inherited through families or amplified by drug taking, the better treatment options and public policy around drugs and drug users can be, she hopes.

The findings appear in the Proceedings of the National Academy of Sciences.

Researchers from the University of Alabama at Birmingham collaborated on the study, which was funded by the National Institute on Drug Abuse, the Office of Naval Research, the Hope for Depression Research Foundation, and the University of Michigan Substance Abuse Research Center.

Source: University of Michigan