Oxytocin is synthesized in the cell bodies of the magnocellular neurones of the paraventricular and supraoptic nuclei of the hypothalamus (Fig. 34a). Other neurones in the same nuclei produce vasopressin (see Chapter 35). The axons of these neurones pass through the median eminence and terminate in close contact with fenestrated capillaries in the posterior pituitary gland. Both oxytocin and vasopressin are synthesized in the rough endoplasmic reticulum of the cell body, together with proteins called neurophysins. Oxytocin and its neurophysin protein (called neurophysin I) are packaged together in the Golgi apparatus in the same vesicle or secretory granule. The vesicle also contains the enzymes which cleave oxytocin from the neurophysin as the granules migrate along the axon towards the nerve terminal. Neurophysin I is occasionally referred to as the oxytocin transport protein. There is evidence that if the neurophysins fail to be synthesized, then oxytocin and vasopressin do not reach the posterior pituitary. Chemically, oxytocin is a nonapeptide with a disulphide bridge between its two cysteine residues (Fig. 34a).
Oxytocin neurones send axons not only to the posterior pituitary, but also to higher centres in the brain, where the hormone may serve as a neurotransmitter mediating certain forms of behaviour (see below).
Excitatory cholinergic and inhibitory neurones make synaptic contact with the neurosecretory oxytocin neurones in the paraventricular and supraoptic nuclei. Oxytocin is secreted from the nerve terminal by exocytosis, as a result of increased intra-cellular Ca2+, due to depolarization of the axon membrane, which opens calcium channels. Oxytocin applied to the oxytocin neurones in the hypothalamus stimulates oxytocin release from the nerve terminals.
Oxytocin binds to its receptor on target cells, for example the mammary myoepithelium, uterine smooth muscle and brain and activates the phospholipase/inositol triphosphate (PLC/IP3) system, which increases intracellular calcium and the effect of the hormone is expressed.
Parturition. Oxytocin induces contraction of the smooth muscle of the uterine myometrium, during the last 2–3 weeks of pregnancy (Fig. 34a and c). This may be due to a sharp increase in the numbers of oxytocin receptors, whose synthesis is stimulated by the high circulating concentrations of estrogens present in the third trimester of pregnancy. The trigger for oxytocin receptor synthesis may be the increasing ratio of estrogen to progesterone, as concentrations of the latter hormone diminish during labour. Oxytocin is released from the posterior pituitary during the course of labour and parturition, possibly as a result of the dilation of the cervix, which sends afferent fibres to the central nervous system. It is not yet known whether the release of oxytocin is the cause of the onset of labour in humans.
Milk ejection. Suckling stimulates sensory nerve endings in the nipple and areolus of the breast, and the impulses are conducted along afferent fibres to the spinal cord (Fig. 34a), where they ascend via the lateral, dorsal and ventral spinothalamic tracts to the midbrain, from where excitatory fibres project directly to the oxytocin neurones in the hypothalamus and oxytocin is released from the pituitary gland. Oxytocin binds to receptors on the myoepithelial cells of the mammary tissue, causing contraction of their muscle-like fibres, and this increases intramammary pressure. Milk ejection from the breasts can occur even before the suckling reflex is initiated. The sound of a human baby crying may be sufficient to cause milk ‘let down’ (Fig. 34b).
Maternal behaviour can be elicited by oxytocin (Fig. 34c). If virgin rats are administered oxytocin directly into the cerebrospinal fluid, they exhibit maternal behaviour to foster pups. If the rats are ovariectomized, oxytocin no longer has the effect, which can be restored if the ovariectomized rats are first given injections of estrogen. Infusion of oxytocin into the ventricles of the brain of virgin rats or non-pregnant sheep rapidly induces maternal behaviour. Administration into the brain of oxytocin antibodies or of oxytocin antagonists prevents the maternal rat from accepting her pups. These experiments suggest that maternal behaviour results, at least in part, from exposure of the brain to high concentrations of estrogens, priming it for the action of oxytocin, which stimulates maternal behaviour, either as a neurotransmitter, or as a hormone or both. This is not to say that oxytocin is absolutely required for maternal behaviour. Rats in which the oxytocin gene was disrupted were still able to exhibit maternal behaviour, although suckling was severely impaired. Other possible roles for oxytocin. Oxytocin is released from the human posterior pituitary during coitus and orgasm, but the significance of this, if any, remains unknown. Oxytocin may be involved in the facilitation of sperm transport. Oxytocin may also be involved in the mediation of, for example, anxiety and pair bonding in primates.
Oxytocin release is inhibited by, for example, acute stress, through the mediation of adrenal catecholamines, which bind to oxytocin neurones and inhibit oxytocin release.