title: Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse.
abstract: Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter. We demonstrate that the SERT Met172 substitution induces an ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. Moreover, in these mice, we observed reduced SERT occupancy, a diminished ability to prolong 5-HT clearance, and a reduced capacity to elevate extracellular 5-HT. Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. Our findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Nackenoff
authors.forename: Linda D
authors.initials: LD
authors.lastname: Simmler
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Baganz
authors.affiliation: Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
authors.forename: Randy D
authors.identifier: 0000-0002-2182-6966
authors.initials: RD
authors.lastname: Blakely
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013440:Sulfides; D012701:Serotonin; D000078784:Vortioxetine
keywords: SERT Met172; Serotonin; antidepressant; mouse; vortioxetine