Researchers at Stanford University School of Medicine have discovered a molecular mechanism responsible for one of the most important symptoms of major depression: anhedonia, the loss of the ability to experience pleasure.
While the study was conducted in mice, the brain circuit involved in this new pathway is largely identical between rodents and humans, increasing the odds that the findings could point toward new therapies for depression and other disorders, the researchers note.
While as many as one in six Americans is likely to suffer depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of patients, noted Robert Malenka, MD, PhD, and the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences.
“This may be because all current medications for depression work via the same mechanisms,” he said. “They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms.”
Malenka is senior author of the new study, published in Nature, which shows how a hormone known to affect appetite turns off the brain’s ability to experience pleasure when an animal is stressed.
The hormone, melanocortin, signals the brain’s reward circuit, which has evolved to guide animals toward resources, behaviors and environments — such as food, sex and warmth — that enhance their prospects for survival.
The specific causes of depression are not well understood, the researchers said. There is no laboratory test for depression — the diagnosis is based mainly on patients’ own reports of lethargy, despondency, despair and disturbances of appetite and sleep — but a core symptom is anhedonia, also known as the blues.
In the search for new compounds to combat depression, however, drug developers typically have used tests of mouse behaviors that may not truly reflect this key feature of depression — and may also limit the search for effective drugs, according to Malenka.
For this study, Malenka and his colleagues instead tested a mouse’s ability to experience enjoyment. In another departure from more common practice in studies of depression, the scientists conducted their behavioral measurements after exposing the mice to chronic stress rather than simply placing otherwise normal mice in a single stressful situation.
The researcher specifically notes the “forced swim” test, where scientists throw a rodent into water and measure how long it takes for the animal to give up trying to swim — an outcome assumed to indicate “behavioral despair.”
The researchers say this assumption is a red herring because it imputes a state of mind — despair — to rats and mice.
Instead, the researchers decided to use chronically stressed mice to explore the effect of a naturally occurring molecule, melanocortin.
“A few scattered studies had suggested that chronic stress increased melanocortin levels in the brain,” Malenka said. “And it was known that stressed animals have heightened numbers of receptors for melanocortin in the nucleus accumbens,” which is a key region of the reward circuit.
What wasn’t yet known, however, is whether melanocortin actually affected the nucleus accumbens or how, he said. “We wanted to find out, because we were wondering if by modulating melanocortin’s activity with a drug we could relieve or prevent a major symptom of depression,” he explained.
Malenka’s team subjected mice to chronic stress by confining them for three to four hours a day in small tubes with holes in them for air flow over a period of eight days.
They then subjected the mice to the sucrose-preference test often used in laboratories. Researchers note that if you give mice a choice between water and water containing dissolved sugar, they usually go for the sugar water. However, chronically stressed mice lose that preference, just as people suffering depression lose joy in their lives.
Malenka reports that the stressful confinement clearly reduced the mice’s preference for sugar water over plain water. The animals also lost about five percent to 10 percent of their body weight, another frequent symptom of depression, he said.
The researchers also used electrophysiological, biochemical and gene-transferring techniques to delineate the precise brain circuitry involved in the stress-induced behavioral changes down to the molecular level.
For example, the scientists scrutinized the nerve cells in the nucleus accumbens that contain receptors for melanocortin.
The scientists found that both chronic stress and the direct administration of melanocortin diminished the signaling strength of some of the tiny electrochemical contacts, known as synapses, on a set of nerve cells in the nucleus accumbens that contain receptors for melanocortin. When these receptors were removed, the same stressful confinement no longer caused changes in those nerve cells’ synapses.
At the same time, despite the weeklong stressful experience, the mice’s sugar preference was returned to normal and the animals no longer lost weight.
The researchers then substituted cocaine for water. They got the same results with cocaine as they had in their earlier experimentation, which is further evidence that the chronic stress-induced changes in the brain due to melanocortin action cause an animal to lose its ability to experience pleasure, the researchers said.
Additionally, Malenka and his associates demonstrated that the brain circuit transmitting melanocortin’s depression-like message to the reward circuitry operates independently of the circuitry responsible for making a mouse give up when the game gets too tough. Manipulating the melanocortin-associated pathway in the nucleus accumbens had no effect on the mice’s performance in the forced-swim test, the researchers said, noting the stressed mice gave up just as easily when the melanocortin receptors in their nucleus accumbens were depleted as when they weren’t.
The melanocortin pathway is already of interest to drug companies, Malenka said, because it appears to be involved in appetite disorders. This means companies already have melanocortin mimics and inhibitors at their disposal that could be used in clinical tests to determine whether managing patients’ melanocortin signaling relieves anhedonia, he said.
This could have implications beyond treatments for depression because anhedonia manifests in other neuropsychiatric syndromes, such as schizophrenia, as well as in terminally ill people who have given up hope, he concluded.