Investigating Plasma Membrane Monoamine Transporter (PMAT) as a Target for Development of Novel Antidepressant Treatments for Juveniles

Abstract

Depression is a psychiatric illness that affects individuals of all ages, yet only two antidepressants are approved to treat depression in children – both belong to the selective serotonin reuptake inhibitor (SSRI) class. Moreover, children 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 OCTs and PMAT, produces antidepressant‐like effects when SERT function is either genetically or pharmacologically impaired. However, it is unknown whether OCTs and/or PMAT may be useful targets for therapeutic interventions in juveniles. In contrast to adults, our preliminary studies show that D22 has antidepressant‐like effects in juvenile (postnatal day 21 (P21)) wild‐type mice, suggesting that OCTs and/or PMAT may be functionally upregulated in juvenile mice. Since PMAT has a higher affinity for serotonin compared to OCTs, we investigated the antidepressant‐like effects of D22 in male and female P21 PMAT wild‐type (+/+) and constitutive PMAT knockout (−/−) mice and found the antidepressant‐like effects of D22 were lost in P21 PMAT−/− mice. Using in vivo chronoamperometry, we examined serotonin clearance kinetics in CA3 region of hippocampus in P21 PMAT+/+ and PMAT−/− mice. Across serotonin concentrations ranging from 0.25 to 1.5 micromolar, we found no difference in serotonin clearance rate between genotypes. These data suggest that either a) these concentrations of serotonin are insufficient to engage PMAT, and/or b) SERT, or other OCT isoform, is upregulated in constitutive PMAT−/− mice. In either case, detection of PMAT‐dependent serotonin clearance would be obscured. Ongoing studies are investigating the effect of D22 on serotonin clearance in juveniles and adults over a range of serotonin concentrations, as well as evaluating PMAT expression in brain as a function of age and PMAT genotype. Together, these studies will expand our understanding of differences in serotonin transport mechanisms between juvenile and adult brain, and will aid in discovery of novel targets for the development of antidepressants with improved therapeutic efficacy for children suffering from depression.Support or Funding InformationThis work was supported by the National Institutes of Health R01 MH106978 to LCD