Age-Related Differences in Serotonin Clearance: Novel Targets for Antidepressants

Depression is a major public health problem for which the majority of patients are not effectively treated. This problem is exacerbated further in children and adolescents for whom only two antidepressant drugs are currently approved. Both belong to the selective serotonin (5-HT) reuptake inhibitor (SSRI) class of antidepressant, and act by blocking high-affinity uptake of 5-HT from extracellular fluid via the serotonin transporter(SERT). The therapeutic utility of SSRIs is thought to be triggered by downstream events that occur in response to their ability to increase extracellular levels of 5-HT. However, our studies using adult mice show that the ability of SSRIs to inhibit 5-HT uptake is greatly limited by the presence of non-SERT, decynium-22 (D22) sensitive transporters for 5-HT. Thus, by preventing extracellular 5-HT rising to therapeutically useful levels, non-SERT transporters provide a mechanistic basis for limited therapeutic efficacy of SSRIs. D22 inhibits activity of organic catio transporters (OCTs) and the plasma membrane monoamine transporter (PMAT). OCTs and PMAT are expressed in adult brain, but their impact on serotonergic neurotransmission may be even greater in juvenile and adolescent brain, particularly if their expression and activity is disproportionately greater than SERT. However, little is known about expression or function of SERT in juvenile and adolescent brain, and nothing is known about the expression and function of OCTs and PMAT at these young ages. Not surprisingly, nothing is known about the relation among SERT, OCTs and PMAT in juvenile, adolescent, and adult brain and antidepressant response. The goals of the proposed studies are to fill these critical gaps in knowledge by (1) providing a systematic profile for SERT expression and function in juvenile, adolescent, and adult mice and importantly, determining how expression and function of OCTs and PMAT varies with that of SERT, and (2) determining how the antidepressant-like response to blockers of these transporters differs among juvenile, adolescent, and adult mice. Our preliminary data support the hypothesis that OCTs and/or PMAT play a more prominent role in 5-HT uptake during childhood and adolescence than in adulthood, and may be useful targets for antidepressant drugs, especially in this young population. Studies proposed here will afford new insight into mechanisms regulating 5- HT uptake in brain during childhood and adolescence, compared with adulthood. Given the strong link between dysfunction in 5-HT signaling and many psychiatric disorders, depression being prominent among them, elucidating mechanisms controlling 5-HT uptake in children and adolescents compared with adults will further our understanding of the etiological bases for these disorders and importantly, will guide the development of improved treatments. PUBLIC HEALTH RELEVANCE: Depression is a major public health problem, especially in young people, because the few antidepressants that are available to treat children and adolescents are less effective than in adults. These antidepressants block uptake of serotonin in brain by the serotonin transporter. Studies proposed here will investigate the emerging role of other, "non-traditional" transporters for serotonin in limiting the therapeutic effects of antidepressants, especially in children and adolescents, with the goal to guide development of more effective antidepressants to treat young people.