The most widely prescribed antidepressants - medicines such as Prozac, Lexapro and Paxil - work by blocking the serotonin transporter, a brain protein that normally clears away the mood-regulating chemical serotonin. Or so the current thinking goes.
That theory about how selective serotonin reuptake inhibitors (SSRIs) work can now be put to the test with a new mouse model developed by neuroscientists at Vanderbilt University.
These mice, described in the online edition of the Proceedings of the National Academy of Sciences (PNAS), express a serotonin transporter that has been genetically altered so that it does not respond to many SSRIs or cocaine.
In addition to testing the theory about how SSRIs work, the new mouse model could lead to the development of entirely new classes of antidepressant medications, said Randy Blakely, Ph.D., Allan D. Bass Professor of Pharmacology and Psychiatry at Vanderbilt and senior author of the PNAS paper.
"Many antidepressants have been shown to target other proteins besides the serotonin transporter and - their efficacy in treating depression takes many weeks to develop," Blakely said. "There is likely a lot that we don't know about how these drugs act."
To generate the mouse model, Blakely and colleagues at Vanderbilt and the University of Texas Health Science Center at San Antonio first determined exactly which parts of the serotonin transporter protein interact with SSRIs. They took advantage of the fact that the fruit fly expresses a serotonin transporter that is relatively insensitive to the drugs.
By changing the protein's amino acid building blocks, they converted parts of the human serotonin transporter into its fruit fly equivalent, and in so doing identified the single amino acid required for potent binding to many SSRIs as well as to cocaine.