It takes weeks or months for the effect of most antidepressants to kick in, time that can feel like an eternity to those who need the drugs the most. But new research suggests that a protein called p11, previously shown to play a role in a person's susceptibility to depression, activates a serotonin receptor in the brain known for producing
a rapid antidepressant response. If scientists could develop drugs to target this receptor, they might produce an effect in as little as two days.'
The finding, reported this month in The Journal of Neuroscience by Rockefeller University's Paul Greengard, Jennifer L. Warner-Schmidt and colleagues in Sweden, solidifies p11 as a key determinant of vulnerability to depression and may lead investigators to new treatments.
Previous research by Greengard, who is Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience, and coauthor Per Svenningsson established p11 as a key signaling molecule for a neurotransmitter known as serotonin, which has long been linked to mood. They also showed that the interaction between p11 and serotonin influences an individual's susceptibility to depression and his or her response to antidepressant treatments. (They later showed that p11 and serotonin also play a role in the symptoms of advanced Parkinson's disease.)
These earlier studies focused on the serotonin 1B receptor. For the new study, Greengard, Svenningsson and their colleagues looked at p11's interaction with another receptor known as serotonin 4, which has been shown to produce a rapid antidepressant response in rodent models of depression. Because serotonin 4 is expressed outside the brain, particularly in the gastrointestinal system, scientists have had difficulty homing in on it to evaluate its potential as an effective therapeutic target.
Using transgenic mice that express a green fluorescent protein when the serotonin 4 receptor is switched on, the researchers showed that p11 and serotonin 4 are expressed together in regions of the brain that are associated with depression.