Serotonin neurons of the caudal raphe nuclei contribute to sympathetic recovery following hypotensive hemorrhage

Abstract

Serotonin is thought to contribute to the syncopal-like response that develops during severe blood loss by inhibiting presympathetic neurons of the rostroventrolateral medulla (RVLM). Here, we tested whether serotonin cells activated during hypotensive hemorrhage, i.e., express the protein product of the immediate early gene c-Fos, are critical for the normal sympathetic response to blood loss in unanesthetized rats. Serotonin-immunoreactive cells of the raphe obscurus and raphe magnus, parapyramidal cells of the B3 region, subependymal cells of the ventral parapyramidal region, and cells of the ventrolateral periaqueductal gray region were activated by hypotensive hemorrhage, but not by hypotension alone. In contrast to findings in anesthetized animals, lesion of hindbrain serotonergic cells sufficient to produce >80% loss of serotonin nerve terminal immunoreactivity in the RVLM accelerated the sympatholytic response to blood loss, attenuated recovery of sympathetic activity after termination of hemorrhage, and exaggerated metabolic acidosis. Hindbrain serotonin lesion also attenuated ventilatory and sympathetic responses to stimulation of central chemoreceptors but increased spontaneous arterial baroreflex sensitivity and decreased blood pressure variability. A more global neurotoxic lesion that also eliminated tryptophan hydroxylase-immunoreactive cells of the ventrolateral periaqueductal gray region had no further effect on the sympatholytic response to blood loss. Together, the data indicate that serotonin cells of the caudal hindbrain contribute to compensatory responses following blood loss that help maintain oxygenation of peripheral tissue in the unanesthetized rat. This effect may be related to facilitation of chemoreflex responses to acidosis.

Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders

“…For example, hypotensive haemorrhage triggered a significant increase of tph2 expression in rat caudal midline medulla [32], just in accordance with the involvement of 5-HT neurons of the caudal raphe nuclei in hypotensive hemorrhage [33], whereas hypoxia led to a significant decline of tph2 expression in the hypothalami of the Atlantic croaker [34]. In addition, exposure of rats [35] and mice [36] to repeated forced swim and chronic variable stress, respectively, resulted in elevated tph2 expression in the midbrain, while early-life experience (maternal separation) and adulthood stressful events (social defeat) interacted to affect Tph2 mRNA expression in rat raphe [37].…”

Daily voluntary exercise alters the cardiovascular response to hemorrhage in conscious male rats

“…Thus, there may also have been parallel changes in vagal efferent drive that were counter-balanced by peripheral changes (Ludbrook and Graham 1984). It should be noted however, that HRV variables, particularly the HF component are also modulated by changes in respiration (Cottin 2004), thus it remains possible that another effect of daily EX is to modulate the respiratory response to HEM (Li 2008; Kung 2010). …”

“…The recovery from HEM has been linked to the modulation multiple systems, including elevated levels of circulating vasopressin (Hock 1984), activation of the arterial chemoreflex (Kung 2010), and increases in sympathetic drive (Osei-Owusu and Scrogin 2006). In the present study at the end of HEM, both EX and SED animals showed immediate signs of recovery with spontaneous increases in HR and MAP.…”

Regional differences in serotonin content in the nucleus of the solitary tract of male rats after hypovolemia produced by polyethylene glycol

“…In part, this difficulty has arisen from the use of hypotensive hemorrhage to produce volume loss (e.g., [34, 35, 36]), as it is difficult to separate effects attributable to volume loss from those attributable to hypotension. Another complication involves experimental manipulations that employed selective 5-HT receptor agonists and antagonists [23, 24, 25, 26], with the resultant receptor subtype specific effects.…”

“…Taken together, the tissue content and immunolabeling results are consistent with the accumulation of 5-HT in neural elements and, in particular, in synaptic specializations located on neural fibers that terminate in or pass through the cNTS. Typically, the 5-HT would be thought to originate from one of the brainstem raphe cell groups and, in fact, the NTS does receive projections from raphe 5-HT cell groups (e.g., [34, 35]). Moreover, severe hypotensive hemorrhage accompanied by hypercapnia activates 5-HT neurons in some raphe cell groups [34, 35, 36].…”