Abstract
Altered activity of the serotonin transporter (SERT) transporter has been hypothesized to contribute to major depression, anxiety, obsessive compulsive disorder (OCD), and autism. A principal component of this theory is the belief that SERTs are the primary target for selective serotonin reuptake inhibitor (SSRI)‐class antidepressants, as well as many tricyclic antidepressants (TCA‘s). Cocaine also has high affinity for SERT, though the role of 5HT reuptake blockade in psychostimulant action is unclear. Cross‐species analysis of SERT has identified a substitution that, in vitro, results in a dramatic loss of affinity for cocaine, several SSRI‘s and TCA‘s with no appreciable effect on 5HT transport (Henry, L.K., et al., 2006). Here we report the introduction of the I172M substitution into the SERT locus of 129Sv mice by homologous recombination. Preliminary competition uptake analysis of midbrain synaptosomal preparations from mice carrying this substitution demonstrate a nearly 100 fold shift in fluoxetine potency as predicted from in vitro studies. In this presentation, I will report on efforts to define the full impact of the I172M mutation on ex vivo SERT pharmacology as well as initial behavioral actions lost or preserved following SSRI or psychostimulant treatments.
Published Version
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