Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter

• Published in: Pharmacological research Vol. 140; pp. 56 - 66
• Main Authors: Brindley, Rebecca L., Bauer, Mary Beth, Walker, L. Anne, Quinlan, Meagan A., Carneiro, Ana M.D., Sze, Ji-Ying, Blakely, Randy D., Currie, Kevin P.M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2019
• Subjects: Adrenal chromaffin cell; Adrenal gland; Adrenal Glands - metabolism; Animals; Antidepressive Agents; Catecholamines; Female; Male; Mesencephalon - metabolism; Mice, Transgenic; Models, Animal; Rhombencephalon - metabolism; Serotonin; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin transporter; Spinal Cord - metabolism; Sympathetic nervous system; Tyrosine 3-Monooxygenase; OCT; Serotonin; 3′-UTR; Catecholamines; Adrenal chromaffin cell; Sympathetic nervous system; SERTΔTH; SSRI; SERT; Serotonin transporter; Th; 5-HIAA; IRES; Escitalopram oxalate (CID: 146571); Adrenal gland; 5-HT; SERTfl/fl; wt; HPLC
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2018.06.008

[Display omitted] Adrenal chromaffin cells comprise the neuroendocrine arm of the sympathetic nervous system and secrete catecholamines to coordinate the appropriate stress response. Deletion of the serotonin (5-HT) transporter (SERT) gene in mice (SERT−/− mice) or pharmacological block of SERT function in rodents and humans augments this sympathoadrenal stress response (epinephrine secretion). The prevailing assumption is that loss of CNS SERT alters central drive to the peripheral sympathetic nervous system. Adrenal chromaffin cells also prominently express SERT where it might coordinate accumulation of 5-HT for reuse in the autocrine control of stress-evoked catecholamine secretion. To help test this hypothesis, we have generated a novel mouse model with selective excision of SERT in the peripheral sympathetic nervous system (SERTΔTH), generated by crossing floxed SERT mice with tyrosine hydroxylase Cre driver mice. SERT expression, assessed by western blot, was abolished in the adrenal gland but not perturbed in the CNS of SERTΔTH mice. SERT-mediated [3H] 5-HT uptake was unaltered in midbrain, hindbrain, and spinal cord synaptosomes, confirming transporter function was intact in the CNS. Endogenous midbrain and whole blood 5-HT homeostasis was unperturbed in SERTΔTH mice, contrasting with the depleted 5-HT content in SERT−/− mice. Selective SERT excision reduced adrenal gland 5-HT content by ≈ 50% in SERTΔTH mice but had no effect on adrenal catecholamine content. This novel model confirms that SERT expressed in adrenal chromaffin cells is essential for maintaining wild-type levels of 5-HT and provides a powerful tool to help dissect the role of SERT in the sympathetic stress response.