title: Antidepressant-like effects and basal immobility depend on age and serotonin transporter genotype.
abstract: Monoamine uptake inhibitors are common treatments for depression; however, the therapeutic efficacy of these drugs varies widely. Two factors that are commonly linked to clinical outcome are age and serotonin transporter (SERT) genotype. Mouse models provide powerful tools to study consequences of age and genotype on antidepressant-like efficacy; however, to date, systematic studies of this nature are lacking. Here, we used the tail suspension test (TST), a preclinical assay for antidepressant efficacy, to gain insight into age and SERT genotype dependency of immobility time in the TST under control conditions (saline injection) and in response to the tricyclic antidepressant, desipramine (DMI). Immobility after saline injection in juvenile, adolescent, adult, mature adult and middle-aged mice (postnatal days 21, 28, 90, 210 and 300, respectively) significantly increased with age; however, the rate of increase was slower for SERT null (-/-) mice than for wild-type (+/+) or heterozygote (+/-) mice. Desipramine reduced immobility across ages and SERT genotypes. Middle-aged, but not adult, SERT(-/-) mice were significantly more sensitive to DMI than age-matched SERT(+/+) or SERT(+/-) mice. Desipramine was less potent in middle-aged SERT(+/+) and SERT(+/-) mice than in adult SERT(+/+) or SERT(+/-) mice. Regardless of age, DMI's maximal effects were greater in SERT(-/-) mice than in SERT(+/+) or SERT(+/-) mice. These results show that immobility time in the TST varies as a function of age and SERT genotype, underscoring the utility of the TST as a potential model to examine age- and SERT genotype-dependent influences on antidepressant response.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
mesh_terms: D000367:Age Factors; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology* / Q000627:therapeutic use; D003891:Desipramine / Q000494:pharmacology* / Q000627:therapeutic use; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D003891:Desipramine
keywords: Adolescent; antidepressant; basal immobility; desipramine; efficacy; juvenile; middle-age; serotonin transporter; tail suspension test; tricyclic