Ghrelin, a stress-induced hormone, primes the brain for post traumatic stress disorder (PTSD), says an October 15, 2013 news release by Anne Trafton, MIT News Office, "Ghrelin, a stress-induced hormone, primes the brain for PTSD." The new Massachusetts Institute of Technology (MIT) study finds that ghrelin, produced during stressful situations, primes the brain for post-traumatic stress disorder. About a dozen years ago, scientists discovered that a hormone called ghrelin enhances appetite.
Dubbed the "hunger hormone," ghrelin was quickly targeted by drug companies seeking treatments for obesity — none of which have yet panned out. The new MIT study finds that ghrelin, produced during stressful situations, primes the brain for post-traumatic stress disorder. But ghrelin also makes you feel hungry. And that's not all. Ghrelin also could make you want to drink more alcoholic beverages.
MIT neuroscientists have now discovered that ghrelin's role goes far beyond controlling hunger. The researchers found that ghrelin released during chronic stress makes the brain more vulnerable to traumatic events, suggesting that it may predispose people to posttraumatic stress disorder (PTSD). Drugs that reduce ghrelin levels, originally developed to try to combat obesity, could help protect people who are at high risk for PTSD, such as soldiers serving in war, says Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, and senior author of a paper describing the findings in the Oct. 15 online edition of Molecular Psychiatry.
"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," says Goosens, according to an October 15, 2013 news release by Anne Trafton, MIT News Office, "Ghrelin, a stress-induced hormone, primes the brain for PTSD." Goosens is also a member of MIT's McGovern Institute for Brain Research. Lead author of the paper is Retsina Meyer, a recent MIT PhD recipient. Other authors are McGovern postdoc Anthony Burgos-Robles, graduate student Elizabeth Liu, and McGovern research scientist Susana Correia.
Stress and fear
Stress is a useful response to dangerous situations because it provokes action to escape or fight back. However, when stress is chronic, it can produce anxiety, depression and other mental illnesses. At the Massachusetts Institute of Technology (MIT), Goosens discovered that one brain structure that is especially critical for generating fear, the amygdala, has a special response to chronic stress. The amygdala produces large amounts of growth hormone during stress, a change that seems not to occur in other brain regions.
In the new paper, Goosens and her colleagues found that the release of the growth hormone in the amygdala is controlled by ghrelin, which is produced primarily in the stomach and travels throughout the body, including the brain. Ghrelin levels are elevated by chronic stress. In humans, this might be produced by factors such as unemployment, bullying, or loss of a family member. Ghrelin stimulates the secretion of growth hormone from the brain; the effects of growth hormone from the pituitary gland in organs such as the liver and bones have been extensively studied. However, the role of growth hormone in the brain, particularly the amygdala, is not well known.
The researchers found that when rats were given either a drug to stimulate the ghrelin receptor or gene therapy to overexpress growth hormone over a prolonged period, they became much more susceptible to fear than normal rats. Fear was measured by training all of the rats to fear an innocuous, novel tone. While all rats learned to fear the tone, the rats with prolonged increased activity of the ghrelin receptor or overexpression of growth hormone were the most fearful, assessed by how long they froze after hearing the tone. Blocking the cell receptors that interact with ghrelin or growth hormone reduced fear to normal levels in chronically stressed rats.
When rats were exposed to chronic stress over a prolonged period, their circulating ghrelin and amygdalar growth hormone levels also went up, and fearful memories were encoded more strongly. This is similar to what the researchers believe happens in people who suffer from PTSD. "When you have people with a history of stress who encounter a traumatic event, they are more likely to develop PTSD because that history of stress has altered something about their biology. They have an excessively strong memory of the traumatic event, and that is one of the things that drives their PTSD symptoms," Goosens explains in the news release.
New drugs, new targets
Over the last century, scientists have described the hypothalamic-pituitary-adrenal (HPA) axis, which produces adrenaline, cortisol (corticosterone in rats), and other hormones that stimulate "fight or flight" behavior. Since then, stress research has focused almost exclusively on the HPA axis.
After discovering ghrelin's role in stress, the MIT researchers suspected that ghrelin was also linked to the HPA axis. However, they were surprised to find that when the rats' adrenal glands — the source of corticosterone, adrenaline, and noradrenaline — were removed, the animals still became overly fearful when chronically stressed. The authors also showed that repeated ghrelin-receptor stimulation did not trigger release of HPA hormones, and that blockade of the ghrelin receptor did not blunt release of HPA stress hormones. Therefore, the ghrelin-initiated stress pathway appears to act independently of the HPA axis. "That's important because it gives us a whole new target for stress therapies," Goosens says.
Pharmaceutical companies have developed at least a dozen possible drug compounds that interfere with ghrelin
Many of these drugs have been found safe for humans, but have not been shown to help people lose weight. The researchers believe these drugs could offer a way to vaccinate people entering stressful situations, or even to treat people who already suffer from PTSD, because ghrelin levels remain high long after the chronic stress ends. PTSD affects about 7.7 million American adults, including soldiers and victims of crimes, accidents, or natural disasters. About 40 to 50 percent of patients recover within five years, Meyer says, but the rest never get better.
The researchers hypothesize that the persistent elevation of ghrelin following trauma exposure could be one of the factors that maintain PTSD. "So, could you immediately reverse PTSD? Maybe not, but maybe the ghrelin could get damped down and these people could go through cognitive behavioral therapy, and over time, maybe we can reverse it," Meyer says in the news release.
Working with researchers at Massachusetts General Hospital, Goosens' lab is now planning to study ghrelin levels in human patients suffering from anxiety and fear disorders. They are also planning a clinical trial of a drug that blocks ghrelin to see if it can prevent relapse of depression. The U.S. Army Research Office, the Defense Advanced Research Projects Agency, and the National Institute of Mental Health funded the research.
Ghrelin and how it influences the desire to eat and drink alcohol
According to a University of Michigan press release, "A Faculty of 1000: Biology and Medicine" evaluation of a 2009 new study done by the research scientists at the University of Gothenburg in Sweden examined how one stomach-produced hormone influences the desire to eat and also consume alcohol could be switched off to control drinking problems, according to a press release issued today by the University of Michigan based on the earlier study. Also helpful is another study, "Why Some Continue to Eat When Full: Researchers Find Clues."
How do you stop your desire to drink alcoholic beverages? This intriguing paper suggests that the hormone ghrelin facilitates in mice the motivation to drink alcohol (in addition to its well-known role in strengthening the motivation to eat food).
Ghrelin is a hormone typically released from the stomach into the bloodstream at the beginning of meals that is known to promote appetite and food intake. Here, one of the study's authors, Jerlhag E, and colleagues report that it may also promote alcohol intake.
Scientists revealed how microinjections of ghrelin into the ventral tegmentum or into cerebral ventricles increased behavioral consumption of alcohol. On the opposite side, microinjections or systemic administration of receptor-blocking antagonists reduced alcohol consumption.
This may reflect more than an appetite for calories, because the authors report that mutant knockout mice lacking GHS-R1A ghrelin receptors further showed deficits in alcohol-induced conditioned place preference, and related stimulation of dopamine release in the nucleus accumbens. The big question here is do these results suggest a role for the effects of ghrelin on the brain in the motivation for alcohol consumption?
The 2009 study, "Requirement of central ghrelin signaling for alcohol reward," was published in the Protocols of the National Academy of Sciences, USA. July 7, 2009. The authors are Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, and Engel JA, Section for Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
The study, carried out by Jerlhag et al. at the University of Gothenburg in Sweden, showed that the hormone ghrelin, typically released by the stomach and known to promote appetite and therefore the intake of food, also influences the consumption of alcohol
The results, published in The Proceedings of the National Academy of Sciences of the USA, showed that mice injected with ghrelin and then given the choice of alcohol or water to drink, were more likely to choose alcohol. At the same time, mice treated with ghrelin antagonists, as well as mice with the hormone, ghrelin's receptor removed, were resistant to the effects of alcohol.
University of Michigan researchers say that the ghrelin-injected mice showed something more than a typical appetite for calories in choosing alcohol. See the findings and how the results of the study might influence treatment strategies for alcoholism. Scientists were looking for results that might suggest a role for the effects of ghrelin on the brain in the motivation for alcohol consumption. If ghrelin is stopped, the big question is, will alcoholism be stopped? But what happens when the body is deprived of ghrelin if it's needed for other necessary body functions? That's the big question.
The study's abstract noted that the "stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice.
"By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists.
"Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol." The researchers' data suggest that "central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders." For further information, you may wish to read the study's abstract. Check out an abstract of the original paper by Jerlhag et al. Or see the site, "Requirement Of Central Ghrelin Signaling For Alcohol Reward."