SCIENTISTS have found a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While the Stanford University School of Medicine study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.
Additionally, opinion leaders hailed the study‘s inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers. Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, is the senior author of the new study, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain“s ability to experience pleasure when an animal is stressed. This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviours and environments - such as food, sex and warmth - that enhance their prospects for survival. Malenka‘s team decided to use chronically stressed mice to explore the activity of a naturally occurring molecule, melanocortin.
“A few scattered studies had suggested that chronic stress increased melanocortin levels in the brain,” he said. “And it was known that stressed animals have heightened numbers of receptors for melanocortin in the nucleus accumbens,” a key region of the reward circuit. If this all-important circuit is working properly, it doles out pleasure when an animal achieves a desirable goal or experiences rewarding stimuli, such as food or sex. If it``s not working properly, anhedonia is the result. But it wasn``t yet known, Malenka continued, whether melanocortin actually affected the nucleus accumbens or how.
Malenka“s team subjected mice to chronic stress by confining them, for three to four hours a day, in small conical tubes with holes in them for air flow over a period of eight days. This stressful confinement clearly reduced the mice“s preference for sugar water over plain water. (The animals also lost about 5-10 percent of their body weight, a frequent depression symptom.) 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.