Project Summary

Randy D. Blakely, Ph.D. (Distinguished Investigator 2005) of Vanderbilt University, will establish and evaluate “knock-in” mice with mutations in the serotonin transporter SERT, a presynaptic membrane protein targeted with high-affinity by selective serotonin reuptake inhibitors (SSRIs)-type antidepressants like Prozac (fluoxetine), Celexa (citalopram), and Paxil (paroxetine). The neurotransmitter serotonin (5-HT) plays a critical role in central modulatory circuits which control arousal, motivation, mood and libido. The actions of 5-HT are terminated by the 5-HT transporter (SERT, 5HTT). Dr. Blakely notes that while SSRIs target SERTs with higher affinity, other targets have been reported and may contribute to both the therapeutic action of a drug, and/or the side effect profiles. While SERT knock-out mice have been generated, they have displayed significant compensatory reductions in 5-HT, altered 5-HT metabolism and shifted receptor sensitivities. Thus, new animal models are needed to address these issues. Dr. Blakely now proposes to develop the “knock-in” mice, which can then serve as models 1) to determine definitively SERT specificity in the behavioral actions of SSRIs, 2) to identify additional targets for SSRIs, whose identity is currently obscured by SERT, 3) to develop non-SERT based therapeutics for the treatment of depression, and 4) specify 5-HT linked gene regulatory cascades that ensue from SERT inhibition in vivo. Dr. Blakely’s project may lead to increased understanding of the mechanisms which lead to depression, as well as improved antidepressant medications.

Program Area: MOOD DISORDERS\Unipolar Depression

Search Again