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.
And this theory about how selective serotonin reuptake inhibitors (SSRIs) work can now be put to the test, thanks to the new research.
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, Allan D. Bass, senior author of the study.
"Many antidepressants have been shown to target other proteins besides the serotonin transporter and ... their efficacy in treating depression takes many weeks to develop. There is likely a lot that we don't know about how these drugs act," said Blakely.
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.
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.
As predicted, the genetically-modified mice displayed normal serotonin transporter levels, and their transporter exhibited normal activity in clearing serotonin from the synapses between nerve cells.
But the mice did not respond to Prozac or Lexapro, indicating that the transporter is indeed the specific target of these medications for blocking serotonin inactivation.
The findings have been published in the online edition of the Proceedings of the National Academy of Sciences (PNAS). (ANI)