Research Magazine 2006

An answer to addiction?

brain on pills

“The devil made me do it” may be the line that still casts most blame after an all-nighter. But when it comes to drug addiction, depression or even disorders like Parkinson’s disease, Linda Perrotti knows who—or what—the real evil may be.

Rest rarely comes for the psychology assistant professor, nor are there breaks in the research that began nearly five years ago during postdoctoral studies at UT Southwestern Medical Center at Dallas. That’s how all-consuming her work is with a protein called DeltaFosB.

Using rats as guinea pigs, Dr. Perrotti delves into what these genes, when expressed inside the human brain, can do to a person.

“What I’m more interested in is how hormones affect genes like DeltaFosB and can act to enhance or inhibit different sorts of behavior,” she said. “And what we’ve discovered with DeltaFosB is that it can make people more apt to look for drugs.”

The whole idea of DeltaFosB can be a bit confusing, Perrotti admits. The gene confounded researchers for years, begging the scientific question that she is answering today.

Many genes like DeltaFosB appear in response to stimuli such as chronic stress. Within a few hours, most of the genes return to normal levels. However, DeltaFosB persists in great numbers even months later.

“We have proposed that DeltaFosB may function as a sustained molecular switch that mediates some of the more persistent adaptations of the brain in response to chronic stimulation,” Perrotti said. She adds that virtually all drugs of abuse—cocaine, opiates, nicotine—induce production of DeltaFosB and the adverse behavior that it exacerbates.

“What are hormonal effects on this molecule? After 21 days in a rat brain, we still see a high level of DeltaFosB, and thus the molecular switch is still activated. This may bring about the cortical inhibition of the ability to decisively determine what to do and not to do typically seen in addicts.”

Perrotti proposes that addicts have a “miswiring,” a faulty projection across the brain’s neurotransmitters, that causes substance abusers “to make very bad decisions.”

“When we look at molecular changes, they seem to be permanent changes in memory and behavior,” she said. “The user eventually doesn’t have free will any longer. At first, drug use is volitional, but when you see a rat bang on a lever for a dose of cocaine, over food or water or sex, you know there’s a little something more to it.”

Perrotti’s research shows promise. She hopes one day to develop pharmacotherapies to treat not only drug addiction, but depression. The answer, she believes, lies in manipulation of this persistent DeltaFosB protein.

“Males and females have different responses to different drugs that lead to different patterns of use, relapse and overdose,” she said. “I’d like to know what might work best for either sex in regard to drug treatment and other issues we face as humans.

“It’s easy for me to sit behind my desk and make observations, but it becomes very personal when you think about it in terms of a friend or family member. You can work with rats and get lost in your molecule, but I try never to forget that there’s a human population out there.”

— David Van Meter