Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles
Melodi A. Bowman,
Jorge A. Gomez,
Nathan C. Mitchell,
Anne M. Wells,
Melissa Vitela,
Kyra M. Clarke,
Rebecca E. Horton,
Wouter Koek,
Lynette C. Daws
Affiliations
Melodi A. Bowman
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Jorge A. Gomez
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Nathan C. Mitchell
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Anne M. Wells
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Melissa Vitela
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Kyra M. Clarke
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Rebecca E. Horton
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Wouter Koek
Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Lynette C. Daws
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs’ ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults.
