title: Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression.
abstract: Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Horton
authors.forename: Deana M
authors.initials: DM
authors.lastname: Apple
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Baganz
authors.forename: Sonia
authors.initials: S
authors.lastname: Cano
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Mitchell
authors.forename: Melissa
authors.initials: M
authors.lastname: Vitela
authors.forename: Georgianna G
authors.initials: GG
authors.lastname: Gould
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D055724:Electrophysiological Phenomena; D016666:Fluvoxamine / Q000494:pharmacology; D019417:Hindlimb Suspension; D006624:Hippocampus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D050479:Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D020230:Serotonin Syndrome / Q000523:psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000928:Antidepressive Agents; D016666:Fluvoxamine; D050479:Neurotransmitter Transport Proteins; D050814:Octamer Transcription Factor-3; D011804:Quinolines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C494174:Pou5f1 protein, mouse; C100254:pseudoisocyanine