Oxytocin redux.

CONSIDERED FOR MANY YEARS to be primarily a circulating hormone contributing to parturition and lactation, over the past three decades oxytocin’s broader spectrum of bioactivity has revealed important roles in the control of anterior pituitary hormone secretion, the stress response, social behaviors, cardiovascular control, fluid and electrolyte homeostasis, and appetite regulation. Most of these observations clearly reflect actions not related to release from the neurohypophysis, but instead release from distinct neuronal populations within the central nervous system (CNS) and perhaps even actions of peptide produced outside of the CNS. No longer overshadowed by the intense focus on vasopressin, oxytocin’s anorexigenic and autonomic effects, together with the emerging evidence of its actions on energy expenditure and social cognition, have taken center stage, and the peptide has become recognized to be an important homeostatic regulatory factor. Soon after its original characterization by Vigneaud and colleagues (14) in 1953, the smooth muscle actions of oxytocin were recognized to be critical for efficient parturition and milk let down (12, 35). Even before its characterization, physiologists had recognized that extracts of posterior pituitary glands stimulated uterine contractions (12). With the realization that distinct receptors for vasopressin and oxytocin existed, and yet some promiscuity in terms of ligand specificity could be demonstrated, much work in the middle of the 20th century was directed at identifying the unique actions of oxytocin and vasopressin. It came as no surprise that overlapping activities were observed considering the common evolutionary ancestries of not only the two peptides themselves but also their cognate receptors (18). The classical view of neurohypophysial oxytocin release was challenged when nascent immunohistochemical approaches began to demonstrate broad projections of oxytocinpositive cell fibers throughout the CNS (9), and autoradiographic techniques revealed the presence of oxytocin binding sites in hypothalamic and extrahypothalamic sites (20, 53), many not seemingly related to the conventional physiological actions of the circulating hormone (Fig. 1). Indeed oxytocinpositive fibers are not only present in the internal layer of the rat median eminence but also in the external layer where they intermingle with the fenestrated capillary endothelial cells of the developing hypophysial-portal vasculature (50), suggesting a true neuroendocrine action of the nonapetide in the anterior pituitary gland. Indeed, Gibbs (17) demonstrated the presence of oxytocin in rat hypophyseal portal plasma in levels more than 10 times higher than those in the peripheral circulation (17). By that time oxytocin had been demonstrated to stimulate prolactin secretion at the level of the lactotroph itself (26), an action that was subsequently shown to be physiologically relevant (51). Surprisingly, oxytocin also exerted hypothalamic actions to inhibit prolactin secretion, suggesting a negative feedback mechanism balancing appropriate hormone secretion under selective physiological states (49). An even bigger surprise was the revelation that oxytocin interacted with hypothalamic circuits controlling gonadotropin secretion. Those studies were the first to employ plant lectin-based cytotoxin approaches to determine the physiological relevance of the pharmacological action of a neuropeptide in hypothalamic function (50). The ricin-oxytocin cytotoxin targeting methodology was also applied to the study of oxytocin’s central action to inhibit salt appetite (3, 4). Those authors not only demonstrated the physiological relevance of the CNS actions of oxytocin in osmotically driven salt appetite but also presented evidence for a sodium receptor mechanism independent of the osmotic mechanisms regulating salt appetite (4). Subsequent studies by Morris and colleagues (44) employing oxytocin gene-knockout mice further evidenced a physiologically relevant role for oxytocin in salt appetite. Where oxytocin acts in CNS to express these actions remains unknown; however, Verbalis and colleagues (39) did speculate that these actions of oxytocin might reflect a broader action of the peptide to inhibit solute ingestion. The realization that oxytocin-positive neurons (9, 34, 52, 54, 55) innervated CNS sites known to be important in cardiovascular function suggested autonomic actions. Indeed the broad distribution of oxytocin receptor mRNA expression throughout the CNS, but specifically in brain stem sites important to cardiovascular and respiratory control, supported that hypothesis (61). Although controversial in the beginning (15, 42), oxytocin has been demonstrated to activate the autonomic system when administered into the cerebroventricles (41) or directly into the rostral ventrolateral medulla (27). Oxytocin gene knockout mice were reported to display mild hypotension (30, 44). Oxytocin-positive neurons have been observed to colocalize with sympathetic preganglionic neurons in the thoracic spinal cord (57), and the peptide has been demonstrated to activate these neurons in vitro (13). Local application of oxytocin increased heart rate in anesthetized rats, and the ability of PVN stimulation to increase heart rate was blocked by oxytocin antagonists administered into the same area of spinal cord (64). More recently, the ability of oxytocin antagonist pretreatment in the lateral ventricle to abrogate the actions of CRH and nesfatin-1 to elevate mean arterial pressure when administered also into the lateral ventricle suggested that oxytocin not only acts directly to activate sympathetic outflow but also interacts with a variety of other neural circuits influencing autonomic function (66). The interaction of oxytocin with CRH and stress circuitry (11, 54, 66) may underlie some of the prosocial actions of oxytocin (63, 67) as well as the appetitive actions of the peptide (37). Address for reprint requests and other correspondence: W. K. Samson, Saint Louis University, 1402 South Grand Boulevard, St. Louis, MO 63104 (e-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 311: R710–R713, 2016; First published August 10, 2016; doi:10.1152/ajpregu.00307.2016. Editorial