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  • The present study showed for

    2024-06-20

    The present study showed, for the first time, that hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine, and isocorynoxeine in yokukansan can inhibit the 5-HT3 receptor current. These data indicate that part of the effect of yokukansan against the behavioral and psychological symptoms of dementia might come from antagonism of the 5-HT3 receptor. Moreover, yokukansan might be a useful treatment for the side effects of 5-HT3 antagonists, such as emesis and addiction.
    Introduction The serotonin transporter (SERT; SLC6A4) is one of the main routes for clearing extracellular serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system. As such, SERT plays an important role in controlling serotonergic neurotransmission/neuromodulation. Underscoring this, genetic variations that alter the expression or activity of SERT are linked to several neurobehavioural disorders (e.g. depression, anxiety, autism), which are often treated by drugs that target SERT (e.g. selective serotonin reuptake inhibitors - SSRIs) (for reviews see (Daws and Gould, 2011, Muller et al., 2016, Murphy et al., 2008, Ye and Blakely, 2011)). Although much attention has focused on serotonergic signaling in the CNS, the majority of 5-HT is produced in the periphery, primarily in the gut where it has multiple actions (Gershon, 2013). SERT plays diverse physiological roles in the periphery by modulating 5-HT signaling and homeostasis. Of relevance for this paper, SERT is prominently expressed in adrenal chromaffin salinomycin which comprise the neuroendocrine arm of the sympathetic nervous system (Schroeter et al., 1997). However, the role(s) of SERT and 5-HT signaling in the peripheral sympathetic nervous system remain poorly understood. Sympathoadrenal chromaffin cells synthesize and release a cocktail of catecholamines (primarily adrenaline and noradrenaline) and neuropeptides to mediate the response to physiological and emotional stressors (Livett et al., 1981, Winkler and Westhead, 1980). Preganglionic splanchnic nerves relay the central drive and trigger electrical excitability, Ca2+entry through voltage-gated Ca2+channels, and subsequent exocytosis of secretory vesicles (stimulus-secretion coupling) (Garcia et al., 2006). A variety of G protein coupled receptors (GPCRs) expressed by chromaffin cells detect and respond to neuronal, autocrine/paracrine, and circulating (endocrine) mediators to modulate stimulus-secretion coupling (Currie, 2010, Garcia et al., 2006, Jewell and Currie, 2013). In mammals, adrenal chromaffin cells lack the rate limiting enzyme for synthesis of 5-HT, tryptophan hydroxylase. However, they do contain a small amount of 5-HT (≈750 fold lower abundance than adrenaline) which appears to be the result of SERT-mediated uptake (Kent and Coupland, 1984, Linder et al., 2009, Tjurmina et al., 2002, Verhofstad and Jonsson, 1983). This 5-HT is presumably packaged into secretory vesicles by the vesicular monoamine transporter; otherwise it would be subject to metabolism by monoamine oxidase. Thus, one role of SERT in the adrenal gland could be to endow a serotonergic phenotype onto these catecholaminergic cells. SERT−/− mice display an exaggerated sympathoadrenal response to restraint stress (i.e. a greater increase in plasma adrenaline compared to wild-type controls) (Tjurmina et al., 2002), and treatment with SSRIs enhanced the sympathoadrenal response to hypoglycemia in rodents and humans (Briscoe et al., 2008, Sanders et al., 2008). Taken together, these data suggest that serotonergic signaling helps control the sympathetic stress response, but it is unclear if this reflects local serotonergic signaling within the adrenal gland and/or altered central drive due to loss/block of SERT in the CNS. In this paper we confirmed that mouse adrenal glands contain 5-HT (≈750 fold lower than adrenaline) and this was dramatically reduced in SERT−/− mice with no change in the catecholamine content. We show for the first time that SERT modulated the ability of 5-HT1A receptors to inhibit stimulus-secretion coupling. Receptor activation reduced the number of vesicular fusion events but not the amount or kinetics of transmitter release from each vesicle. The inhibition did not involve voltage-gated Ca2+ channels or K+ channels, the usual targets for inhibitory GPCR signaling. Spike charge and kinetics were reduced in SERT−/− cells compared to wild-type cells, indicating that SERT has an additional, distinct effect. Overall, our data reveal a novel role for SERT, and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response.