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Beyond Prozac: Generation and characterization of SSRI Insensitive Transgenic Mice
Author(s) -
Thompson Brent J,,
Jessen Tammy,
Henry L. Keith,
Gamble Karen L.,
Chisnell Peter J.,
McMahon Douglas G.,
Blakely Randy D.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.942.7
Subject(s) - serotonin transporter , pharmacology , serotonergic , citalopram , serotonin , potency , antidepressant , fluoxetine , reuptake inhibitor , serotonin reuptake inhibitor , chemistry , biology , endocrinology , biochemistry , in vitro , receptor , hippocampus
Altered activity of the serotonin transporter (SERT) transporter has been hypothesized to contribute to major depression, anxiety, obsessive compulsive disorder, 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). Cross‐species analysis of SERT has identified a substitution (I172M) 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). We have introduced the I172M substitution into the SERT locus of 129S6 mice by homologous recombination. As predicted this substitution has no impact on 5HT transport and these animals exhibit no overt behavioral phenotype. Behavioral studies revealed a reduction in responsiveness to citalopram in the tail suspension test, as well as reduced responsiveness to fluoxetine and citalopram in the forced swim test. Ex vivo analysis of forebrain synaptosomal 5HT transport from mice carrying this substitution demonstrate ~1,000 fold shift in citalopram potency, ~12 fold shift in fluoxetine potency and ~32 fold shift in cocaine potency. In contrast, paroxetine displayed less than a 2 fold shift in potency. These findings are complemented by ex vivo midbrain slice recordings of serotonergic neurons in the dorsal raphe, which show a significant shift in SSRIs induced autoinhibition of neuronal firing. Ongoing efforts aim to define the full impact of the I172M mutation on in vivo and ex vivo SERT pharmacology as well as the effect this loss of SSRI potency has on SSRI induced behavior. Grant Funding Source NARSAD Distinguished Investigator Award, NIDA Award (DA07390) and The Silvio Conte Center for Neuroscience Research at Vanderbilt University (MH078028)