Oxytocin
Biosynthesis
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).
Secretion
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.
Actions
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.
