Oxytocin – a neurotransmitter and a hormone

Oxytocin is a nonapeptide produced in the PVN and the supraoptic nucleus (SON) with- in the hypothalamus. Magnocellular neurons within the SON and PVN project to the neurohypophysis, whence oxytocin is released into the circulation. In addition, a widespread network of parvocellular, oxytocinergic nerve fibers project from the PVN to many areas within the brain. The median eminence, the amygdala, the hippocampus, the olfactory bulb, the striatum, the nucleus accumbens (NA), the raphe nuclei, the locus ceruleus, the vagal motor and sensory nuclei, and the spinal cord are all reached by oxytocinergic fibers (Buijs et al. 1985).

Oxytocin may induce effects in many areas of the brain, as oxytocin receptors are widely distributed in the brain (Freund-Mercier et al. 1987). Recently it has been demonstrated that large quantities of oxytocin are also released from cell bodies and dendrites of oxytocin-producing cells in the SON and PVN. It has therefore been suggested that oxytocin may also reach neurons that are not adjacent to the release sites by diffusion or volume transmission (Ludwig & Leng 2006).

It is well known that the mammary glands and the uterus are richly provided with oxytocin receptors. Oxytocin receptors are, however, also found in many peripheral organs, e.g. in the kidneys, pancreas, stomach, thymus, adipocytes, heart, ventricle and blood vessels (Bonne & Cohen 1975, Elands et al. 1990, McCann et al. 2002, Stock et al. 1990, Stoeckel & Freund-Mercier 1989, Yazawa et al. 1996).

The PVN is also reached by afferent pathways from the NTS, the locus ceruleus, other parts of the hypothalamus, and even from the dorsal horn of the spinal cord, suggesting that the release of oxytocin is controlled from many different areas in the CNS (Swanson & Sawchenko 1980, 1983, Sawchenko & Swanson 1982).

The distribution of afferent and efferent projection patterns and the distribution of oxytocin receptors are similar in females and males (Sawchenko & Swanson 1982, Sofroniew 1983, Swanson & Sawchenko 1980, 1983), but the effects of oxytocin may differ between males and females owing to the effects of sex hormones. Estrogens may increase the release of oxytocin and also the responsiveness and/or number of oxytocin receptors (Schumacher et al. 1993).

Effects of oxytocin in animals

Oxytocin modulates many physiological and behavioral functions. Administration of oxytocin to animals has been demonstrated to induce a multitude of effects, which depend in part on the experimental situation and whether the effects mimic circulating actions of oxytocin or the effects of oxytocin as a neurotransmitter in the CNS.

Oxytocin administered intracerebroventricularly, or in high doses systemically to induce effects in the CNS, has been demonstrated to reduce blood pressure and activity in the HPA axis. The effect of oxytocin on the HPA axis seems to be exerted at many levels (see below and Fig. 9.1). It also influences the release of gastrointestinal hormones, increases nociceptive thresholds, and reduces inflammation and levels of anxiety, as well as inducing calm and stimulating learning.

Figure 9.1 Schematic regulation of the hypothalamopituitary–adrenal (HPA) axis and the inhibition of oxytocin at several levels. ACTH, adrenocorticotropic hormone; CRF, corticotrophin-releasing factor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PVN, paraventricular nucleus of the hypothalamus.

When oxytocin is administered repeatedly long-term effects may be induced. Five daily injections of oxytocin reduce blood pressure and activity in the HPA axis and increase nociceptive thresholds for weeks after the last treatment. In response to repeated treatments oxytocin also influences the levels of gastrointestinal hormones, increases weight gain, and shortens wound healing time. Further, it improves learning by conditioning (Björkstrand et al. 1996, Petersson et al. 1996a,b, 1998, 1999a,b, 2001, Szeto et al. 2008, Uvnäs-Moberg et al. 1992, 1996b, 2000).

Oxytocin knockout mice have an increased release of corticosterone in response to stress and show more anxiety-like behavior, further supporting the role of oxytocin as an anxiolytic and anti-stress agent (Amico et al. 2008). In addition, oxytocin stimulates various kinds of interactive social behavior and bonding between mother and young, and between males and females (Carter 1998).

Oxytocin mediates effects not only via the classic uterine oxytocin receptor, but proba-bly also via oxytocin receptors with other characteristics, as not all oxytocin effects exerted in the brain are blocked by antagonists directed towards the classic oxytocin receptor. Moreover, administration of oxytocin to rats increases α₂-adrenoreceptor function in several brain regions, such as the amygdala, NTS, and locus ceruleus, as measured by autoradiography and electrophysiology. It is likely that this effect underlies some of the oxytocin-induced anti-stress effects (Petersson et al. 2005). Oxytocin also influences cholinergic, serotonergic (5HT), and opioidergic transmission. Some of the long-term effects may be induced by altering the function of these classic signaling systems. In addition, dopamine, opioids, acetylcholine, and 5HT influence the release of oxytocin, and antidepressant drugs, such as serotonin reuptake inhibitors (SSRI), have been shown to release oxytocin (Uvnäs-Moberg et al. 1999).

Taken together, these data show, first, that oxytocin induces a response pattern cha- racterized by anti-stress effects and stimulation of growth and restorative processes (the growth and relaxation response) and also behavioral actions involving calm and increased social behavior (the calm and connection response) (Uvnäs-Moberg 1997, 2003); and second, that the function of the oxytocinergic system is strongly connected with the activity of other, more classic, signaling systems (Bagdy & Kalogeras 1993, Clarke et al. 1978, Crowley et al. 1991, Uvnäs-Moberg et al. 1999, Wright & Clarke 1984).

Effects of oxytocin in humans

Since the beginning of the 19th century oxytocin has been known to stimulate uterine contractions during labor and to induce milk letdown in breastfeeding women, being administered as an infusion to induce or augment labor and as a nasal spray to promote milk letdown. Recently the oxytocin nasal spray has also been administered to men, and several effects have been documented. The oxytocin has an anxiolytic effect and dampens activity in the amygdala. It also reduces activity in the HPA axis, as well as increasing social skills, e.g. the ability to read and evaluate the emotional valence of faces, in both healthy and autistic men. In other studies the administration of oxytocin spray has been demonstrated to increase trust and generosity in men and to reduce abdominal pain in women (Heinrichs et al. 2003, Kosfeld et al. 2005, Ohlsson et al. 2005, Rimmele et al. 2009). Oxytocin administered as an intravenous infusion also reduces anxiety and increases social skills, effects that last for weeks after administration (Hollander et al. 2007, Jonas et al. 2008a).

Thus the administration of oxytocin to humans not only stimulates uterine contractions and milk ejection via circulating effects, but also induces a behavioral and physiological effect pattern. The fact that the effect pattern induced by oxytocin in humans is identical to that induced in animals supports the assumption that oxytocin exerts important regulatory and integrative functions in the brain.

Link between oxytocin and effects induced by non-noxious sensory stimulation

Interestingly, as described above, the administration of oxytocin has been demonstrated to induce an effect spectrum similar to that induced by non-noxious sensory stimulation. As will be described below, oxytocin is also released by non-noxious sensory stimulation, and therefore some of the effects induced by non-noxious sensory stimulation may be mediated by oxytocin released in the brain.

Oxytocin release in response to non-noxious sensory stimulation in animal experiments

It is well known that oxytocin is released during parturition and in response to suckling in lactating animals, and in response to sexual interaction. Oxytocin can, however, also be released in response to other types of non-noxious and pleasant sensory stimulation. When anesthetized rats were exposed to gentle stroking on their backs or afferent electrical stimulation of the sciatic or the vagal nerves, oxytocin levels in plasma increased more than twofold (Stock & Uvnäs-Moberg 1988), and when they were exposed to electroacupuncture, thermal stimulation, or vibration, oxytocin levels increased in both plasma and cerebrospinal fluid (Uvnäs-Moberg et al. 1993).

As mentioned above, 5 minutes of stroking on the abdomen of conscious rats (40 strokes per minute) induces a multitude of behavioral and physiological effects (Box 9.1; note that weight gain is only observed in response to repeated treatments). Oxytocin is also released by this type of stimulation, and the effects of stroking may therefore involve an oxytocinergic mechanism. The elevation of pain threshold and the calming and anxiolytic-like effects caused by stroking on the abdomen are probably exerted in the periaqueductal gray (PAG), amygdala, and LC, by oxytocin released from oxytocinergic fibers originating in the PVN. The connection between oxytocin and the effects induced by stroking are supported by findings that some of the effects, e.g. the elevation of pain threshold, caused by the stroking treatment are blocked if the animals are given an oxytocin antagonist beforehand. In further support of a role for oxytocin in the increase in pain threshold caused by stroking is the fact that increased oxytocin levels in response to stroking have been demonstrated in the PAG, an area in the brain that is of central importance for nociception (Lund et al. 2002).

The effect on pulse rate and blood pressure in response to stroking may be due to an effect in the NTS mediated by oxytocin released from efferent oxytocinergic fibers originating in the paraventricular nucleus of the hypothalamus (PVN), in response to activation of the sensory afferents. The activity of the sympathetic and the parasympathetic nervous system is influenced by this effect, with consequent changes in cardiovascular function.

It is important to state that the effects induced by oxytocin on physiological and behavioral function in response to sensory stimulation are exerted in the brain. Therefore, circulating levels of oxytocin are not always a relevant marker for the release of oxytocin in the brain. Oxytocin may be released into the brain in many situations without a concomitant release into the circulation. A parallel secretion of oxytocin into both the brain and into the circulation has, however, been shown during suckling, feeding, parturition, and vaginocervical stimulation (Kendrick et al. 1986, 1988). In rats, electroacupuncture, vibration, and thermal stimuli significantly increase oxytocin levels in the cerebrospinal fluid (Uvnäs-Moberg et al. 1993).