Ontogeny of Norepinephrine Transporter Expression and Antidepressant-Like Response to Desipramine in Wild-Type and Serotonin Transporter Mutant Mice.
Depression is a major public health concern with symptoms that are often poorly controlled by treatment with common antidepressants. This problem is compounded in juveniles and adolescents, because therapeutic options are limited to selective serotonin reuptake inhibitors (SSRIs). Moreover, therapeutic benefits of SSRIs are often especially limited in certain subpopulations of depressed patients, including children and carriers of low-expressing serotonin transporter (SERT) gene variants. Tricyclic antidepressants (TCAs) offer an alternative to SSRIs; however, how age and SERT expression influence antidepressant response to TCAs is not understood. We investigated the relation between antidepressant-like response to the TCA desipramine using the tail suspension test and saturation binding of [3H]nisoxetine to the norepinephrine transporter (NET), the primary target of desipramine, in juvenile (21 days postnatal [P21]), adolescent (P28), and adult (P90) wild-type (SERT+/+) mice. To model carriers of low-expressing SERT gene variants, we used mice with reduced SERT expression (SERT+/-) or lacking SERT (SERT-/-). The potency and maximal antidepressant-like effect of desipramine was greater in P21 mice than in P90 mice and was SERT genotype independent. NET expression decreased with age in the locus coeruleus and increased with age in several terminal regions (e.g., the cornu ammonis CA1 and CA3 regions of the hippocampus). Binding affinity of [3H]nisoxetine did not vary as a function of age or SERT genotype. These data show age-dependent shifts for desipramine to produce antidepressant-like effects that correlate with NET expression in the locus coeruleus and suggest that drugs with NET-blocking activity may be an effective alternative to SSRIs in juveniles.
Departments of Cellular and Integrative Physiology (N.C.M., M.A.B., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (W.K., L.C.D.), University of Texas Health Science Center, San Antonio, Texas.
Nathan C
NC
Mitchell
Departments of Cellular and Integrative Physiology (N.C.M., M.A.B., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (W.K., L.C.D.), University of Texas Health Science Center, San Antonio, Texas.
Melodi A
MA
Bowman
Departments of Cellular and Integrative Physiology (N.C.M., M.A.B., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (W.K., L.C.D.), University of Texas Health Science Center, San Antonio, Texas.
Georgianna G
GG
Gould
Departments of Cellular and Integrative Physiology (N.C.M., M.A.B., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (W.K., L.C.D.), University of Texas Health Science Center, San Antonio, Texas.
Wouter
W
Koek
Departments of Cellular and Integrative Physiology (N.C.M., M.A.B., G.G.G., L.C.D.), Psychiatry (W.K.), and Pharmacology (W.K., L.C.D.), 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* / Q000627:therapeutic use; D003891:Desipramine / Q000494:pharmacology* / Q000627:therapeutic use; 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; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
D000928:Antidepressive Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D003891:Desipramine