Oxytocin

Oxytocin is a cyclic nonapeptide, a peptide hormone of nine amino acids. Neurons of the hypothalamic paraventricular and supraoptic nuclei make it, and the posterior pituitary releases it in response to stimuli such as suckling and parturition (Gimpl and Fahrenholz, 2001). A disulfide bridge between its two cysteines closes a six-residue ring with a three-residue tail (PubChem CID 439302).

Vincent du Vigneaud's laboratory reported the sequence and proposed this structure in 1953 (du Vigneaud et al., 1953), and he received the 1955 Nobel Prize in Chemistry for work that included the first synthesis of oxytocin and vasopressin (Ottenhausen et al., 2016).

Sequence and synonyms are from PubChem.

Oxytocin research falls into the six areas below. Each summary names its model. The knockout and vole work is animal data; human data come from uterine tissue, intranasal trials and drug labeling.

The oxytocin receptor and its signaling

Expression cloning yielded a human oxytocin receptor cDNA encoding a 388-amino-acid protein with seven transmembrane domains typical of G-protein-coupled receptors. Expressed in Xenopus oocytes, it responded specifically to oxytocin, and its mRNA was very high in myometrium at term (Kimura et al., 1992). A major review describes OXTR as coupled mainly through Gq proteins to phospholipase C-beta, with a high-affinity state that needs magnesium and cholesterol, and lists receptors in kidney, heart, thymus, pancreas and adipocytes (Gimpl and Fahrenholz, 2001). Models: human cDNA, frog oocytes and a review.

Uterine contraction and lactation physiology

In uterine tissue from pregnant women, myometrial oxytocin receptors increased and peaked in early labor, and decidual receptors peaked at parturition; in vitro, oxytocin raised prostaglandin production by decidua but not by myometrium (Fuchs et al., 1982). Knockout mice complicated the picture.

Mice lacking the oxytocin gene were viable and fertile, with normal parturition and maternal behavior, but their pups died soon after birth because the dams could not nurse; oxytocin given to the dams after delivery restored milk ejection (Nishimori et al., 1996). Mice lacking the receptor also delivered normally but showed defects in lactation and maternal nurturing (Takayanagi et al., 2005). Models: human uterine tissue and knockout mice.

Social memory and behavior in mice

Social memory in mice is measured as reduced olfactory investigation of an animal met before. Male mice lacking the oxytocin gene failed to develop it, while non-social olfaction, maze-based spatial memory and startle habituation appeared intact. Oxytocin, but not vasopressin, restored social memory in the knockouts, and an oxytocin antagonist caused a social amnesia-like effect in wild-type mice (Ferguson et al., 2000). In receptor knockouts, male pups emitted fewer ultrasonic vocalizations when isolated, and adult males showed social discrimination deficits and more aggression (Takayanagi et al., 2005). Models: knockout mice; animal data only.

Prairie vole studies

Receptor autoradiography placed oxytocin receptors in the prelimbic cortex, nucleus accumbens and other forebrain areas of the monogamous prairie vole, but mainly in the lateral septum and ventromedial hypothalamus of the polygamous montane vole (Insel and Shapiro, 1992). Ovariectomized female prairie voles given oxytocin into the brain ventricles at 10 or 100 ng per hour during six hours with a male later preferred that partner over an unfamiliar male; peripheral infusion did not, and a central receptor antagonist blocked the effect (Williams et al., 1994).

Yet in three CRISPR lines of prairie voles lacking the receptor, both sexes still preferred their mating partners over strangers, and mothers delivered viable pups that the parents raised to weaning (Berendzen et al., 2023). Models: voles; animal data only.

Intranasal studies in people and the replication debate

In a trust game with human volunteers, investors given intranasal oxytocin showed what the authors called a substantial increase in trust, not explained by general risk-taking (Kosfeld et al., 2005). Many intranasal findings since then have not replicated. A critical review concluded that the trust finding has not replicated well and that the evidence does not robustly tie oxytocin to trust (Nave et al., 2015). A statistical analysis found the field generally underpowered and judged it highly probable that most published intranasal findings do not represent true effects (Walum et al., 2016).

A registered, double-blind, placebo-controlled replication with more than 95 percent power found no effect on trusting behavior in the condition matching the original design (Declerck et al., 2020). In a 24-week randomized phase 2 trial in 290 children and adolescents with autism spectrum disorder, intranasal oxytocin did not differ from placebo on the primary social withdrawal score (P = 0.61) or most secondary outcomes, and adverse events were similar (Sikich et al., 2021). Models: human randomized studies and reviews.