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Review
. 2017 May 17;8(5):943-954.
doi: 10.1021/acschemneuro.7b00026. Epub 2017 Apr 13.

Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response

Affiliations
Review

Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response

Rebecca L Brindley et al. ACS Chem Neurosci. .

Abstract

Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT1A receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca2+ channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.

Keywords: 5-HT receptor; Serotonin transporter; adrenal chromaffin cell; calcium channel; catecholamine; exocytosis; sympathetic nervous system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Relationship between central serotonergic neurons and the sympathetic nervous system
A) Simplified schematic of an adult rodent brain showing serotonergic nuclei (blue) and other brainstem regions (purple) important for central drive to the peripheral sympathetic nervous system. Abbreviations: PAG periaqueductal grey; DR dorsal raphe; MR median raphe; RO raphe obscurus; RM raphe magnus; RP raphe pallidus; PVN paraventricular nucleus of the hypothalamus; RVMM rostral ventromedial medulla; RVLM rostral ventrolateral medulla; A5 A5 noradrenergic cell group. B) Simplified schematic showing that preganglionic sympathetic neurons in the intermediolateral column (IML) of the thoracic spinal cord receive central drive from the RVLM and other brainstem / forebrain regions. The RVLM integrates input from multiple regions but only serotonergic input is shown; this is predominantly inhibitory, although some excitation might also occur. Serotonergic nuclei also send projections directly to the spinal cord to modulate central drive. C) Simplified schematic showing descending projections from the rostral medulla to the preganglionic sympathetic neurons in the intermediolateral column of the thoracic spinal cord (IML). Preganglionic neurons in the IML project to the peripheral sympathetic ganglia and the adrenal medulla. Postganglionic sympathetic neurons project from the ganglia to specific target organs and release norepinephrine (NE) to exert local control. Adrenal chromaffin cells comprise the neuroendocrine arm of the sympathetic nervous system and exert widespread effects by secreting epinephrine (Epi), norepinephrine (NE), and various neuropeptides into the bloodstream.
Figure 2
Figure 2. SERT and serotonergic signaling in adrenal chromaffin cells
A) Schematic showing the mouse adrenal gland (inset) and an adrenal chromaffin cell. SERT can exert multiple effects indicated by the red numbering. 1) SERT is expressed in the adrenal medulla (blue) but not the adrenal cortex. 5-HT is found in the adrenal gland largely due to SERT-mediated uptake. Levels of 5-HT are approximately 1/750th of epinephrine levels. 2) Following SERT-mediated uptake into chromaffin cells 5-HT is packaged into secretory vesicles by the vesicular monoamine transporter (VMAT). 3) Chromaffin cells also express 5-HT1A receptors providing for potential autocrine regulation by 5-HT. 4) SERT constrains the ability of 5-HT to recruit the 5-HT1A receptor signaling pathway. 5) The 5-HT1A receptors reduce catecholamine secretion but this does not involve the typical mechanisms used by inhibitory GPCRs that target chromaffin cell voltage-gated Ca2+ channels (VGCC), K+ channels, or Ca2+ signaling. 6) Other effects of SERT and/or intracellular 5-HT are also possible. B) Known and potential effects of SERT knockout on adrenal chromaffin cells. 1) The adrenal catecholamine content is unaltered in glands from SERT-/- mice, but the 5-HT content is reduced by ≈80%. 2) 5-HT1A receptors are still present and functional, but the loss of cellular 5-HT content presumably prevents autocrine inhibition via these receptors. Conversely, other sources of 5-HT might be expected to more efficiently recruit the 5HT1A receptors as the opposing action of SERT is no longer present. 3) The sympathoadrenal response to acute restraint stress (increase in plasma epinephrine) is exaggerated in SERT knockout mice. 4) There is a failure to upregulate expression of tyrosine hydroxylase (TH) or angiotensin II (Ang II) receptors in response to acute stress in SERT knockouts. 5) The quantal size of unitary vesicular fusion events detected using carbon fiber amperometry is reduced in cells isolated from SERT-/- mice.
Figure 3
Figure 3. Proposed model in which serotonergic inhibition is fine-tuned to control stress-evoked catecholamine secretion
A) During periods of basal or brief stimulation purinergic (and other) receptors that inhibit voltage-gated Ca2+channels mediate autocrine regulation of exocytosis. Left panel: 1) Acetylcholine released from the splanchnic nerve depolarizes chromaffin cells opening voltage-gated Ca2+ channels. 2) The Ca2+ entry triggers exocytosis of catecholamines and other transmitters including ATP, opioids, and 5-HT. Right panel: 3) ATP activates P2Y autoreceptors. 4) Gβγ inhibits the Ca2+ channels, reducing Ca2+ entry and thereby exocytosis. 5) SERT mediated uptake of 5-HT opposes activation of the 5-HT1A receptors so this signaling pathway is not recruited. B) With sustained, stress-like stimulation 5-HT signaling becomes the dominant pathway for autocrine regulation. Left panel: 1-2) As in panel A, acetylcholine released from the splanchnic nerve depolarizes chromaffin cells opening voltage-gated Ca2+ channels and triggering exocytosis. 3) With sustained stimulation PACAP might also be released from the splanchnic nerve and become the main stress mediator activating the chromaffin cells. PACAP acts via PAC1 receptors which recruit additional Ca2+ entry pathways perhaps including CaV3 (T-type) channels and TRPC channels. Right panel: 4) ATP activates P2Y autoreceptors. 5) Inhibition of Ca2+ channels becomes ineffective with strong, sustained depolarization in part because Gβγ dissociates from the channels. 6) The stronger stimulation leads to greater increase in local 5-HT and activation of 5-HT1A receptors. 7) The 5-HT1A receptors inhibit exocytosis by an atypical mechanism independent from cellular excitability / Ca2+ entry that can persist during the sustained stimulation. In this manner, 5-HT signaling becomes the dominant pathway for autocrine regulation.
Figure 4
Figure 4. Schematic depicting use of transgenic mice to selectively excise SERT from the peripheral sympathoadrenal system or central serotonergic neurons
In the “floxed” SERT mouse, SERT is expressed in both central serotonergic neurons and adrenal chromaffin cells (depicted by blue shading). Crossing these mice with Cre driver lines provides a strategy to selectively excise SERT in a tissue specific manner. For example, ePet-Cre drives expression of Cre and excision of SERT in serotonergic neurons of the CNS but not in adrenal chromaffin cells. Conversely, using TH-Cre will result in excision of SERT in the adrenal chromaffin cells but not in CNS raphe neurons.

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