title: Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice.
abstract: Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressant-like effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Baganz
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Horton
authors.forename: Alfredo S
authors.initials: AS
authors.lastname: Calderon
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Munn
authors.forename: Lora T
authors.initials: LT
authors.lastname: Watts
authors.forename: Nina
authors.initials: N
authors.lastname: Koldzic-Zivanovic
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Jeske
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Toney
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D005838:Genotype; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000099254:Organic Cation Transporter 3
chemical_list: D000928:Antidepressive Agents; D027701:Organic Cation Transport Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D000099254:Organic Cation Transporter 3