title: Inhibition of the Serotonin Transporter Is Altered by Metabolites of Selective Serotonin and Norepinephrine Reuptake Inhibitors and Represents a Caution to Acute or Chronic Treatment Paradigms.
abstract: Previous studies of transgenic mice carrying a single isoleucine to methionine substitution (I172M) in the serotonin transporter (SERT) demonstrated a loss of sensitivity to multiple antidepressants (ADs) at SERT. However, the ability of AD metabolites to antagonize SERT was not assessed. Here, we evaluated the selectivity and potency of these metabolites for inhibition of SERT in mouse brain-derived synaptosomes and blood platelets from wild-type (I172 mSERT) and the antidepressant-insensitive mouse M172 mSERT. The metabolites norfluoxetine and desmethylsertraline lost the selectivity demonstrated by the parent compounds for inhibition of wild-type mSERT over M172 mSERT, whereas desvenlafaxine and desmethylcitalopram retained selectivity. Furthermore, we show that the metabolite desmethylcitalopram accumulates in the brain and that the metabolites desmethylcitalopram, norfluoxetine, and desvenlafaxine inhibit serotonin uptake in wild-type mSERT at potencies similar to those of their parent compounds, suggesting that metabolites may play a role in effects observed following AD administration in wild-type and M172 mice.
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences , 1301 North Columbia Road, Grand Forks, North Dakota 58202, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Krout
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences , 1301 North Columbia Road, Grand Forks, North Dakota 58202, United States.
authors.forename: Meghan
authors.initials: M
authors.lastname: Rodriquez
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences , 1301 North Columbia Road, Grand Forks, North Dakota 58202, United States.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Brose
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences , 1301 North Columbia Road, Grand Forks, North Dakota 58202, United States.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Golovko
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences , 1301 North Columbia Road, Grand Forks, North Dakota 58202, United States.
authors.forename: L Keith
authors.identifier: 0000-0001-7998-7589
authors.initials: LK
authors.lastname: Henry
authors.affiliation: Department of Biomedical Sciences, Oakland University William Beaumont School of Medicine , Rochester, Michigan 48309, United States.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Thompson
mesh_terms: D000818:Animals; D015283:Citalopram / Q000031:analogs & derivatives / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000031:analogs & derivatives / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015283:Citalopram; D005473:Fluoxetine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C046304:desmethylcitalopram; C065162:desmethylsertraline; C036139:norfluoxetine
keywords: M172 mouse; SSRI; Serotonin transporter; antidepressants; mass spectrometry; metabolites