@article {Mitchelljpet.116.237305, author = {Nathan C Mitchell and Melodi A Bowman and Georgianna G Gould and Wouter Koek and Lynette C Daws}, title = {Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice.}, elocation-id = {jpet.116.237305}, year = {2016}, doi = {10.1124/jpet.116.237305}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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, where therapeutic options are limited to only two approved antidepressants, both 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 well 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 post-natal [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-/-). Maximal antidepressant-like effect and potency of desipramine were greater in P21 mice than in P90 mice, and were SERT genotype independent. NET expression decreased with age in the locus coeruleus and increased with age in several terminal regions (e.g., CA1 and CA3 regions of 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 TCAs may be an effective alternative to SSRIs.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2016/11/09/jpet.116.237305}, eprint = {https://jpet.aspetjournals.org/content/early/2016/11/09/jpet.116.237305.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }