Ontogeny of SERT Expression and Antidepressant-like Response to Escitalopram in Wild-Type and SERT Mutant Mice.
Depression is a disabling affective disorder for which the majority of patients are not effectively treated. This problem is exacerbated in children and adolescents for whom only two antidepressants are approved, both of which are selective serotonin reuptake inhibitor (SSRIs). Unfortunately SSRIs are often less effective in juveniles than in adults; however, the mechanism(s) underlying age-dependent responses to SSRIs is unknown. To this end, we compared the antidepressant-like response to the SSRI escitalopram using the tail suspension test and saturation binding of [(3)H]citalopram to the serotonin transporter (SERT), the primary target of SSRIs, in juvenile [postnatal day (P)21], adolescent (P28), and adult (P90) wild-type (SERT+/+) mice. In addition, to model individuals carrying low-expressing SERT variants, we studied mice with reduced SERT expression (SERT+/-) or lacking SERT (SERT-/-). Maximal antidepressant-like effects were less in P21 mice relative to P90 mice. This was especially apparent in SERT+/- mice. However, the potency for escitalopram to produce antidepressant-like effects in SERT+/+ and SERT+/- mice was greater in P21 and P28 mice than in adults. SERT expression increased with age in terminal regions and decreased with age in cell body regions. Binding affinity values did not change as a function of age or genotype. As expected, in SERT-/- mice escitalopram produced no behavioral effects, and there was no specific [(3)H]citalopram binding. These data reveal age- and genotype-dependent shifts in the dose-response for escitalopram to produce antidepressant-like effects, which vary with SERT expression, and may contribute to the limited therapeutic response to SSRIs in juveniles and adolescents.
Departments of Physiology (N.C.M., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (L.C.D., W.K.), University of Texas Health Science Center, San Antonio, Texas.
Nathan C
NC
Mitchell
Departments of Physiology (N.C.M., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (L.C.D., W.K.), University of Texas Health Science Center, San Antonio, Texas.
Georgianna G
GG
Gould
Departments of Physiology (N.C.M., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (L.C.D., W.K.), University of Texas Health Science Center, San Antonio, Texas.
Wouter
W
Koek
Departments of Physiology (N.C.M., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (L.C.D., W.K.), University of Texas Health Science Center, San Antonio, Texas daws@uthscsa.edu.
Lynette C
LC
Daws
D000375:Aging / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D009154:Mutation; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*
D000928:Antidepressive Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D012701:Serotonin