Stomaching stress

CAMBRIDGE, Mass.—Scientists at the Massachusetts Institute of Technology have discovered that ghrelin, known as the “hunger hormone,” plays a pivotal role in the widespread issue of posttraumatic stress disorder (PTSD), with recent research suggesting it could have the potential to prevent or treat the condition.

 

Ghrelin is a relatively ‘young’ hormone, first discovered in the early 90s. It is constantly produced in the stomach, and when the body needs to signal that you should eat, production of ghrelin spikes, which is was causes us to feel hunger. Once we’ve eaten, levels of the hormone drop back to background levels.

 

Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, a member of MIT’s McGovern Institute for Brain Research and senior author of the paper, says the team identified the role ghrelin plays in stress while searching for new treatments for PTSD. They first discovered that growth hormone production is increased in the amygdala by chronic stress, Goosens explains, but doesn’t seem to be turned on elsewhere in the brain. So they started looking for something that could regulate growth hormone in the brain.

 

That’s where ghrelin come in. The researchers discovered that one of the major effects of ghrelin in the brain is that it “triggers release of growth hormone from another part of the brain into the circulating bloodstream,” says Goosens.

 

Armed with this information, the researchers exposed rat models to either a drug that stimulated the ghrelin receptor, or gene therapy that served to overexpress growth hormone for long periods of time. Along with a group of normal rats, they were trained to associate a simple tone with fear. Both treated groups of rats developed a much greater sensitivity to fear than normal rats, while blocking the ghrelin or growth hormone receptors reduced fear to normal levels in the chronically stressed rats. In addition, rats exposed to chronic stress proved to have increased circulating levels of ghrelin and amygdalar growth hormone, and proved to encode fearful memories more strongly, a trend believed to occur in human PTSD sufferers.

 

“As you encounter stress, ghrelin levels slowly go up, and then they reach some plateau, and then when stress stops, it’s not like your stomach then goes back to producing the same level of ghrelin that you did before stress,” Goosens explains. “Instead, it keeps churning out more and more ghrelin. And so that elevated ghrelin stays around in rats for months after the stress stops, and for a stress hormone, that’s a really long time. There’s no other stress hormone we know of that’s elevated for that long of a time after stress stops.”

 

The research team also examined the hypothalamic-pituitary-adrenal (HPA) axis—which produces “fight or flight” hormones such as adrenaline and cortisol and has been long the main focus in stress research—to determine its relationship with ghrelin. What they found was that there appeared to be no association between the two when it comes to amplifying stress. Removing the rats’ adrenal glands did not reduce the rats’ fearful reactions when stressed, and stimulating the ghrelin receptor did not trigger the HPA axis to release additional stress hormones, just as blocking the ghrelin receptor didn’t reduce the release of those hormones.

 

Goosens notes that these results seem to imply that the HPA axis does not play a role in the development of PTSD—in rats, at least. It is possible, she says, that both the ghrelin axis and HPA axis are activated in humans with PTSD.

 

“The HPA axis certainly does mediate stress effects, but I think they are stress effects that are probably not central to the key features of PTSD, and our work does not sustain that the HPA axis is the thing you need to target to reduce PTSD,” she adds.

 

Goosens says that moving forward, they will be exploring ghrelin’s potential both as a therapeutic target for those already diagnosed with PTSD and as a preemptive treatment for those at risk of developing the condition, and will test in rat models to see if blocking ghrelin after stress exposure can prevent the development of PTSD. Working in conjunction with a team at Massachusetts General Hospital, Goosens and her will also be studying ghrelin levels in human patients, and planning a clinical trial of a ghrelin-blocking drug to determine its ability to prevent depression relapse.

 

“Perhaps we could give people who are going to be deployed into an active combat zone a ghrelin vaccine before they go, so they will have a lower incidence of PTSD. That’s exciting because right now there’s nothing given to people to prevent PTSD,” Goosens noted in a press release.

 

Any kind of help for PTSD would be a major boon. Some 7.7 million American adults suffer from PTSD, such as soldiers and those who have survived violent crimes or natural disasters. Retsina Meyer, Ph.D., lead author of the paper, noted in a press release that while 40 to 50 percent of PTSD patients recover within five years, the rest never do.

 

Fortunately, the team won’t have to wait for ghrelin antagonists or vaccines to be developed to advance their research, as some dozen drug compounds targeting ghrelin, and at least three vaccines against the hormone, have already been created, thanks to drug developers’ once-high hopes that blocking ghrelin signaling could be an obesity treatment. However, blocking ghrelin hasn’t been shown to have any effect on weight management. Goosens notes that several drug compounds in existence demonstrate high blocking of ghrelin and boast high clinical safety profiles in humans. Vaccines are also an option, though she notes that those haven’t yet achieved clinical results in humans.

 

Given its role in driving hunger could blocking ghrelin too much drive someone to anorexia by removing their desire to eat? It’s a concern, in theory, but Goosens stresses that in their work, the fear-enhancing effects of ghrelin are based on the background levels of the hormone, the constant state, not the meal-related spikes. “What we showed in our rats is we can give doses of ghrelin-receptor antagonists that will block the fear-enhancing effects, but without having any effect on food-seeking behaviors,” says Goosens.

 

The team’s results were published in the Oct. 15 online edition of Molecular Psychiatry.