Abstract
Altered activity of the serotonin transporter (SERT) has been hypothesized to contribute to the etiology of major depression, anxiety, obsessive‐compulsive disorder, and autism. SERTs are thought to be the primary target for selective serotonin reuptake inhibitor (SSRI)‐class antidepressants, as well as many tricyclic antidepressants (TCA's) used to treat these disorders. Previously, we generated mice expressing a SERT variant (SERT I172M) that displays a dramatic loss of SERT affinity for cocaine, several SSRI's and TCA's, without impacting serotonin (5‐HT) transport (Thompson B.J., et al., 2011). Ex vivo forebrain synaptosomal 5‐HT transport assays with mice carrying the I172M substitution reveal an ~1,000 fold shift in citalopram potency, ~150 fold shift in venlafaxine potency, ~ 60 fold shift in sertraline potency and an ~10 fold shift in fluoxetine potency. Here we demonstrate that citalopram's metabolite, desmethylcitalopram, maintains an ~1000 fold shift in potency for SERT I172M, while the metabolites of venlafaxine, sertraline and fluoxetine display much smaller shifts in potency (~40 fold shift for desvenlafaxine, <2 fold shift for desmethysertraline and <2 fold shift for norfluoxetine). These results highlight the importance of considering the actions of drug metabolites. Ongoing studies are examining the effects chronic SSRIs have on gene expression and behavior.Grant Funding Source : UTHSCSA Faculty Startup Funds
Published Version
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