The Serotonin Transporter is Required for Stress-Evoked Increases in Adrenal Catecholamine Synthesis and Angiotensin II AT₂ Receptor Expression

Abstract

High numbers of serotonin transporter (SERT) binding sites and high serotonin (5-HT) content are expressed in the adrenal medulla of wild-type (SERT+/+) mice. Acute restraint stress increases adrenomedullary 5-HT, norepinephrine (NE) and epinephrine (E) release, adrenomedullary tyrosine hydroxylase (TH) mRNA, and angiotensin II AT₂ receptor expression. There are no alterations in adrenal catecholamine content during restraint. In littermate SERT–/– mice, which do not express SERT binding sites, the basal adrenomedullary 5-HT content is significantly reduced and does not increase after stress. The stress-induced increase in plasma E is higher in SERT–/– than in SERT+/+ animals. In SERT–/– mice, the stress-induced increase in expression of TH mRNA does not occur, and as a consequence, adrenal E content decreases, and adrenal E and NE content are lower than that of SERT+/+ mice during restraint. In addition, instead of increased expression, stress induces a profound decrease in the number of adrenomedullary AT₂ receptors in SERT–/– mice. Our results indicate that SERT is necessary for the stress-induced increase in adrenomedullary catecholamine synthesis and AT₂ receptor expression. These data further indicate a close relationship between the adrenomedullary 5-HT and angiotensin II systems, and an important role of adrenomedullary AT₂ receptors in catecholamine synthesis and release during stress.

Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques

“…In this study, PR l͞s females exhibit both increased stress-induced release of ACTH and decreased total cortisol levels. Of note, this pattern of HPA axis output is consistent with findings in serotonin transporter null mutant mice (43,44), in which lower levels of corticosterone in the presence of high levels of ACTH have been proposed to relate in part to dysregulation of paracrine factors controlling adrenocortical sensitivity to ACTH. The ratio of ACTH to cortisol (ACTH:F) represents a crude index of adrenal sensitivity, with a lower ratio denoting higher sensitivity.…”

Maternal stress modulates the effects of developmental lead exposure.

“…Levels of DA, the associated metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT), and the intracellular DA turnover (DOPAC/DA) were determined in frontal cortex, nucleus accumbens, and frontal cortex using methods established in our laboratory (Thiruchelvam et al 2000) and measured at a sensitivity of 2 nA for striatum and frontal cortex and 1 nA for nucleus accumbens. These neurotransmitters have demonstrated sensitivity to Pb (CorySlechta et al 1992(CorySlechta et al , 1996Kala and Jadhav 1995;Pokora et al 1996) and to stress (Armando et al 2003;Bland et al 2003;ChouGreen et al 2003;Finlay and Zigmond 1997;Hanley and Van de Kar 2003;Mangiavacchi et al 2001;Scheggi et al 2002). DA and 5-HT play key roles in the brain regions examined, which include components of both the nigrostriatal and mesolimbic DA systems, thus also allowing some assessment of specificity of effects.…”

5‐hydroxytryptamine in the Cardiovascular System: Focus on the Serotonin Transporter (Sert)

“…Messenger RNA and /or protein are found in the platelets, pulmonary arteries, 4,8 heart, 72 systemic arteries (rat aorta, superior mesenteric and carotid arteries 73 ) and endothelial cells. Other tissues important to blood pressure regulation, such as the nucleus tractus solitarius (NTS 74 ) and the adrenal, 75,76 have only recently been demonstrated to contain SERT.…”

“…76 The ability of promoter variants of SERT to influence the function of the CV system is illustrated by studies in platelets. Platelets from humans that possess the l variant of the SERT promoter have a higher V max than platelets from humans with no l variants.…”