Stress, Neuropeptide Interaction, and Relapse: A Neurobiological Addiction Story

Stress, neurobiologically speaking, is defined as “conditions where an environmental demand exceeds the natural regulatory capacity of an organism” Such stressors might include a debilitating illness or a shake-up at work. Most of us can successfully weather such storms without too much damage, but people with addictions don’t seem to fare as well. Situations that a non-addict may consider a mere nuisance can often overwhelm recovering addicts, making them more likely to relapse and use again. While the link between stress and substance abuse relapse has long been observed, the how’s and why’s of this effect are not well understood. A new study from the University of East Anglia suggests that stress-related relapse may be due to the interactions of small neuropeptides involved with stress and reward behaviors. Better understanding these interactions might help us develop more successful addiction treatments.

A risk of relapse

Rajita Sinha, the founding director of the Yale Stress Center and a psychiatrist at the Yale School of Medicine, says that the combination of anecdotal evidence, observational studies, and work in animal models has long suggested that stress is a trigger for substance abuse relapse.

“When I started looking at the role of stress and why people relapse, we didn’t know much about the mechanisms of it. So we began to study it and try to understand how it was increasing craving and relapse,” she says. “In the case of recovering addicts, their bodies have already adapted to having drugs on board. When you remove the drug, withdrawal pushes them to have what we call abstinence-related symptoms. These are things like sleep problems, anxiety, hyper-arousal and low feelings. Things that tend to give them the compulsion to use again more quickly.”

But Sinha wondered if there might be more to it than that. Her work with former addicts suggested that stressful situations result in the dysregulation in both the brain’s key stress pathways, the hypothalamic-pituitary-adrenal axis (HPA-axis) and the sympatho-adreno-medullary (SAM) system. The products of those pathways, like corticotrophin releasing factor (CRF), a neuropeptide critical to mediating the body’s stress response, differed from the norm not only in people addicted to cocaine but in those addicted to nicotine and to alcohol, too.

“So many people talk about addiction as a function of problems with the brain’s reward system. But what we saw is that drug addiction usurps and hijacks the brain’s stress pathways,” says Sinha. “You want stress pathways to work for you—to identify danger and then allow you to adapt and cope to it. That’s part of being human. But when that system is hijacked is high levels of drug use, it leads to significant damage that leaves you less able to adapt and cope.”

An interactive effect

The changes to CRF regulation in addiction has made it a prime target for drug development. Sinha says that human laboratory screenings have tried to use different CRF antagonist molecules to try to treat addiction, as well as depression and other mood disorders. But they have not, to date, been successful.

“It’s a tough molecule—there are often side effects—and the drug molecule has a different binding potential than natural CRF,” she says. “So when you put it in humans, there are all kinds of challenges which ends up meaning that these molecules aren’t going to be as effective in human treatment as they’ve been in animal studies.”

CRF doesn’t work alone, though, and there are neuropeptides that are linked to both stress and reward behaviors. Peter McCormick, a researcher at the University of East Anglia’s School of Pharmacy, wondered if perhaps the stress/relapse link might involve multiple proteins.

“The literature suggested that CRF could be influencing the function of another neuropeptide, orexin-A. Both have been linked to drug addiction, but it was unclear at the molecular level how the two might be interacting,” he says. “So we thought that perhaps the interaction of CRF and orexin might explain relapse, and we wanted to see whether cocaine might actually disrupt this interaction.”

McCormick and colleagues found that the interaction of these neuropeptides, and their receptors, at the molecular level was disrupted by cocaine, both in in vitro rat brain cells and in live rats. Since those neuropeptides influence both stress response and reward processing, that disruption could explain why addicts are more likely to relapse under stressful conditions. Jonathan Katz, a researcher who studies some of these same neuropeptides at the National Institute on Drug Abuse (NIDA), says it’s a compelling finding

“The interactions that they describe are intriguing, especially if applied to the development of new medications that may help treat drug abuse,” says Katz. “It gives us a new area to explore.”

Not a replacement drug

McCormick is hopeful that, by restoring this important neuropeptide interaction, pharmaceutical companies could develop a drug that would effectively reduce stress-related relapse, especially given the work by researchers like Sinha and Katz. “There’s good evidence that these neuropeptides play an important role. So it seems reasonable to make the jump that what we see in this animal model could be relevant to human treatment,” he says.

Sinha agrees that this interaction is a potential avenue for future treatments—but it will take a lot of work to get there. And to those who worry that such a pharmaceutical agent would simply replace one drug with another in people with addictions, she reminds us that addiction is a brain disease, not a simple matter of strength and willpower.

“There’s a pathology to addiction. It makes profound changes to the brain. In some ways, it’s not unlike depression. But while we accept that it’s okay to treat depression with a medication, we think it’s not right to do so for addiction,” she says. “But it shouldn’t be that way. Addiction changes the brain in a way that requires it to be addressed. Medications may help—so this isn’t about treating a drug with a drug. It’s about finding ways to treat the underlying pathology in the brain that drug addiction has done. And CRF and some of these other molecules of interest may give us a way to do that.”