Abstract
Depression is a major health problem for which most patients are not effectively treated. This problem is further compounded in children and adolescents where only two antidepressants [both selective serotonin reuptake inhibitors (SSRIs)] are currently approved for clinical use. Mouse models provide tools to identify mechanisms that might account for poor treatment response to antidepressants. However, there are few studies in adolescent mice and none in juvenile mice. The tail suspension test (TST) is commonly used to assay for antidepressant-like effects of drugs in adult mice. Here we show that the TST can also be used to assay antidepressant-like effects of drugs in C57Bl/6 mice aged 21 (juvenile) and 28 (adolescent) days post-partum (P). We found that the magnitude of antidepressant-like response to the SSRI escitalopram was less in P21 mice than in P28 or adult mice. The smaller antidepressant response of juveniles was not related to either maximal binding (B max) or affinity (Kd) for [3H]citalopram binding to the serotonin transporter (SERT) in hippocampus, which did not vary significantly among ages. Magnitude of antidepressant-like response to the tricyclic desipramine was similar among ages, as were Bmax and K d values for [3H]nisoxetine binding to the norepinephrine transporter in hippocampus. Together, these findings suggest that juvenile mice are less responsive to the antidepressant-like effects of escitalopram than adults, but that this effect is not due to delayed maturation of SERT in hippocampus. Showing that the TST is a relevant behavioral assay of antidepressant-like activity in juvenile and adolescent mice sets the stage for future studies of the mechanisms underlying the antidepressant response in these young populations.
Highlights
Depression is a major public health problem for which most patients are not effectively treated
The major findings of the present study are first, that the selective serotonin reuptake inhibitor (SSRI) escitalopram and the NET blocker DMI produced antidepressant-like effects in mice as young as P21, the youngest age tested; second, that the magnitude of antidepressant-like response to escitalopram increased with age but was not paralleled by increasing expression or affinity of hippocampal serotonin transporter (SERT); and third that the magnitude of antidepressant-like response to the tricyclic, DMI, as well as expression and affinity of hippocampal NET, did not differ significantly among P21, P28, and adult mice
Our finding that juvenile mice are less sensitive to the antidepressant-like effect of escitalopram than adults, parallels clinical data reporting that, compared to adults, children have a relatively poor therapeutic response to the SSRIs, fluoxetine, and escitalopram, the only two FDA approved antidepressants for this young population
Summary
Depression is a major public health problem for which most patients are not effectively treated This problem is further compounded in children and adolescents by limited pharmacological treatment options (Bylund and Reed, 2007). Despite many reports showing marked differences in the antidepressant response of children and adolescents compared with adults (Bylund and Reed, 2007; Tsapakis et al, 2008; Hetrick et al, 2009, 2010; Hazell and Mirzaie, 2013) there is a paucity of studies investigating the underlying mechanisms. Reasons for the age-dependency of antidepressant response remain poorly understood
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