Investigating Organic Cation Transporter 3 (OCT3) and Plasma Membrane Monoamine Transporter (PMAT) as Targets for Development of New Antidepressant Treatments for Juveniles and Adolescents
Authors: Bowman Melodi A. , Mitchell Nathan C. , Fraser‐Spears Rheaclare , Gould Georgianna , Daws Lynette C. 
Published: June 2021

Depression is a psychiatric illness that affects individuals of all ages, yet only two antidepressants are approved to treat depression in children and adolescents. Both belong to the selective serotonin reuptake inhibitor (SSRI) class. Moreover, children and adolescents are less effectively treated by SSRIs than adults. SSRIs block reuptake of serotonin via the high‐affinity, low‐capacity serotonin transporter (SERT). The resulting increase in extracellular serotonin is thought to initiate a cascade of downstream effects, which underlie the therapeutic utility of SSRIs. However, other transporters also clear serotonin from extracellular fluid, including the low‐affinity, high‐capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT). Our lab has shown that, in adults, decynium‐22 (D22), an inhibitor of OCT1‐3 and PMAT, produces antidepressant‐like effects when SERT function is either genetically or pharmacologically impaired. However, whether OCTs or PMAT may be useful targets for therapeutic intervention in juveniles and adolescents remains unknown. In contrast to adults, our preliminary studies show that D22 has antidepressant‐like effects in juvenile (postnatal day 21 (P21)) SERT+/+ mice, suggesting that OCTs and/or PMAT may be functionally upregulated in juvenile mice. Since antibodies with good selectivity for the OCT subtypes and PMAT are currently lacking, we had D22 custom tritiated ([3H]D22) and used both homogenate binding and autoradiography to quantify expression of D22‐sensitive transporters. We found expression of D22‐sensitive transporters to be increased in both P21 and adolescent (P28) mice, relative to adults (P90). Ongoing studies are utilizing genetic (i.e. OCT3, PMAT knockout) and pharmacological tools in efforts to parse out which D22‐sensitive transporter(s) is/are driving the increase in [3H]D22 binding in juveniles and adolescents. In addition, we are microinjecting corticosterone, a selective OCT3 blocker, and lopinavir, a selective PMAT blocker, into hippocampus to determine their effect on serotonin clearance kinetics using in vivo high‐speed chronoamperometry. Although these drugs have actions elsewhere (i.e. glucocorticoid receptors and proteases, respectively), when combined with use of OCT3 and PMAT knockout mice, are useful pharmacological tools to help decipher contributions of these transporters to serotonin clearance. These studies will expand our understanding of differences between the juvenile, adolescent, and adult brain, and will aid in discovery of novel targets for the development of antidepressants with improved therapeutic efficacy for children and adolescents suffering from depression.

Support or Funding Information

LCD: R01 MH093320 and R01 MH106978 MAB: T32 NS082145

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.