Oxytocin

This is Oxytocin. It is a mammalian neuropeptide hormone best known its roles in sexual reproduction, but has been found to have a role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors. For these reasons, it has come to be known as the "love hormone."

 — with Daviid ORtega Baro.

Oxytocin in a nine amino acid peptide that is synthesized in hypothalamic neurons and transported down axons of the posterior pituitary for secretion into blood. Oxytocin is also secreted within the brain and from a few other tissues, including the ovaries and testes. Oxytocin differs from antidiuretic hormone in two of the nine amino acids. Both hormones are packaged into granules and secreted along with carrier proteins called neurophysins.

Physiologic Effects of Oxytocin

In years past, oxytocin had the reputation of being an "uncomplicated" hormone, with only a few well-defined activities related to birth and lactation. As has been the case with so many hormones, further research has demonstrated many subtle but profound influences of this little peptide, particularly in regards to its effects in the brain. Oxytocin has been implicated in setting a number of social behaviors in species ranging from mice to humans. For example, secretion or administration of oxytocin in humans appears to enhance trust and cooperation within socially-close groups, while promoting defensive aggression toward unrelated, competing groups.

Oxytocin has been best studied in females where it clearly mediates three major effects:

Stimulation of milk ejection (milk letdown): Milk is initially secreted into small sacs within the mammary gland called alveoli, from which it must be ejected for consumption or harvesting. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells which are a prominant target cell for oxytocin. Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns.

Stimulation of uterine smooth muscle contraction at birth: At the end of gestation, the uterus must contract vigorously and for a prolonged period of time in order to deliver the fetus. During the later stages of gestation, there is an increase in abundance of oxytocin receptors on uterine smooth muscle cells, which is associated with increased "irritability" of the uterus (and sometimes the mother as well). Oxytocin is released during labor when the fetus stimulates the cervix and vagina, and it enhances contraction of uterine smooth muscle to facilitate parturition or birth.

In cases where uterine contractions are not sufficient to complete delivery, physicians and veterinarians sometimes administer oxytocin ("pitocin") to further stimulate uterine contractions - great care must be exercised in such situations to assure that the fetus can indeed be delivered and to avoid rupture of the uterus.

Establishment of maternal behavior: Successful reproduction in mammals demands that mothers become attached to and nourish their offspring immediately after birth. It is also important that non-lactating females do not manifest such nurturing behavior. The same events that affect the uterus and mammary gland at the time of birth also affect the brain. During parturition, there is an increase in concentration of oxytocin in cerebrospinal fluid, and oxytocin acting within the brain plays a major role in establishing maternal behavior.

Evidence for this role of oxytocin come from two types of experiments. First, infusion of oxytocin into the ventricles of the brain of virgin rats or non-pregnant sheep rapidly induces maternal behavior. Second, administration into the brain of antibodies that neutralize oxytocin or of oxytocin antagonists will prevent mother rats from accepting their pups. Other studies support the contention that this behavioral effect of oxytocin is broadly applicable among mammals.

While all of the effects described above certainly occur in response to oxytocin, doubt has recently been cast on its necessity in parturition and maternal behavior. Mice that are unable to secrete oxytocin due to targeted disruptions of the oxytocin gene will mate, deliver their pups without apparent difficulty and display normal maternal behavior. However, they do show deficits in milk ejection and have subtle derangements in social behavior. It may be best to view oxytocin as a major facilitator of parturition and maternal behavior rather than a necessary component of these processes.

Both sexes secrete oxytocin - what about its role in males?Males synthesize oxytocin in the same regions of the hypothalamus as in females, and also within the testes and perhaps other reproductive tissues. Pulses of oxytocin can be detected during ejaculation. Current evidence suggests that oxytocin is involved in facilitating sperm transport within the male reproductive system and perhaps also in the female, due to its presence in seminal fluid. It may also have effects on some aspects of male sexual behavior.

Control of Oxytocin Secretion

The most important stimulus for release of hypothalamic oxytocin is initiated by physical stimulation of the nipples or teats. The act of nursing or suckling is relayed within a few milliseconds to the brain via a spinal reflex arc. These signals impinge on oxytocin-secreting neurons, leading to release of oxytocin.

If you want to obtain anything other than trivial amounts of milk from animals like dairy cattle, you have to stimulate oxytocin release because something like 80% of the milk is available only after ejection, and milk ejection requires oxytocin. Watch someone milk a cow, even with a machine, and what you'll see is that prior to milking, the teats and lower udder are washed gently - this tactile stimulation leads to oxytocin release and milk ejection.

A number of factors can inhibit oxytocin release, among them acute stress. For example, oxytocin neurons are repressed by catecholamines, which are released from the adrenal gland in response to many types of stress, including fright. As a practical endocrine tip - don't wear a gorilla costume into a milking parlor full of cows or set off firecrackers around a mother nursing her baby.

Both the production of oxytocin and response to oxytocin are modulated by circulating levels of sex steroids. The burst of oxytocin released at birth seems to be triggered in part by cervical and vaginal stimulation by the fetus, but also because of abruptly declining concentrations of progesterone. Another well-studied effect of steroid hormones is the marked increase in synthesis of uterine (myometrial) oxytocin receptors late in gestation, resulting from increasing concentrations of circulating estrogen.

Oxytocin (Greek, “quick birth”) is a mammalian hormone that also acts as a neurotransmitter in the brain.

In humans, oxytocin is thought to be released during hugging, touching, and orgasm in both sexes. In the brain, oxytocin is involved in social recognition and bonding, and may be involved in the formation of trust between people and generosity. [1][2][3]

In women, it is released in large amounts after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. Synthetic oxytocin is sold as medication under the trade names Pitocin and Syntocinon as well as generic oxytocin.

Actions of oxytocin within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the blood-brain barrier. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum and brainstem.

• Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[12] reflecting actions in the hypothalamus and spinal cord.
• Bonding. In the Prairie Vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males.[13] In people, plasma concentrations of oxytocin have been reported to be higher amongst people who claim to be falling in love.[citation needed] Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans.
• Autism. A 1998 study found significantly lower levels of oxytocin in blood plasma of autistic children.[14] A 2003 study found a decrease in autism spectrum repetitive behaviors when oxytocin was administered intravenously.[15] A 2007 study reported that oxytocin helped autistic adults retain the ability to evaluate the emotional significance of speech intonation.[16]
• Maternal behavior. Sheep and rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin female sheep show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [17]
• Increasing trust and reducing fear. In a risky investment game, experimental subjects given nasally administered oxytocin displayed “the highest level of trust” twice as often as the control group. Subjects who were told that they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk-aversion.[18] Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[19] There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.
• Affecting generosity by increasing empathy during perspective taking. In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80% but has no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experimental explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants which role they would be in.[20]
• According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms.[21]
• Preparing fetal neurons for delivery. Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.[22]
• Certain learning and memory functions are impaired by centrally administered oxytocin.[12]. Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks. [23]
• MDMA (ecstasy) may increase feelings of love, empathy and connection to others by stimulating oxytocin activity via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans.[24]

Peripheral (hormonal) actions of oxytocin

The actions of oxytocin are mediated by specific, high affinity oxytocin receptors. The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland.

• Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be ‘let down’ into a collecting chamber, from where it can be extracted by compressing the areola and sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
• Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition is normal.[4]
• The relationship between oxytocin and human sexual response is unclear. At least two non-controlled studies have found increases in plasma oxytocin at orgasm – in both men and women.[5][6] The authors of one of these studies speculated that oxytocin’s effects on muscle contractibility may facilitate sperm and egg transport.[5] Murphy et al. (1987), studying men, found that oxytocin levels were raised throughout sexual arousal and there was no acute increase at orgasm. [7] A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted that these changes “may simply reflect contractile properties on reproductive tissue.”[8]
• Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More important, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of oxytocin can result in hyponatremia.
• Oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation. [9][10] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[4]
• Modulation of hypothalamic-pituitary-adrenal axis activity. Oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin. [11]

Drug forms of oxytocin

Synthetic oxytocin is sold as medication under the trade names Pitocin and Syntocinon and also as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, and therefore must be administered by injection or as nasal spray. Oxytocin has a half-life of typically about three minutes in the blood. Oxytocin given intravenously does not enter the brain in significant quantities – it is excluded from the brain by the blood-brain barrier. There is no evidence for significant CNS entry of oxytocin by nasal spray. Oxytocin nasal sprays have been used to stimulate breastfeeding but the efficacy of this approach is doubtful[25].

Injected oxytocin analogues are used to induce labor and support labor in case of non-progression of parturition. It has largely replaced ergotamine as the principal agent to increase uterine tone in acute postpartum haemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to increase milk production. The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors; this drug is registered in many countries to suppress premature labour between 24 and 33 weeks of gestation. It has fewer side-effects than drugs previously used for this purpose (ritodrine, salbutamol and terbutaline).

Some have suggested that the trust-inducing property of oxytocin might help those who suffer from social anxieties, while others have noted the potential for abuse with confidence tricks. [26]

Synthesis, storage and release of oxytocin

Oxytocin is made in magnocellular neurosecretory cells in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and is released into the blood from the posterior lobe of the pituitary gland. Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.

In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.

Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.

Oxytocin is also synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of Prostaglandin-F2alpha to cause regression of the corpus luteum.

Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone (CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

References

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2. ^ Zak, P.J. Stanton, A.A., Ahmadi, A. 2007. Oxytocin increases generosity in humans. PLoS ONE 2(11): e1128. [1]

3. ^ Angela A. Stanton 2007. Neural Substrates of Decision-Making in Economic Games. Scientific Journals International 1(1):1-64. [2]

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5. ^ a b Carmichael MS, Humbert R, Dixen J, Palmisano G, Greenleaf W, Davidson JM (1987). “Plasma oxytocin increases in the human sexual response,” J Clin Endocrinol Metab 64:27-31 PMID 3782434

6. ^ Carmichael MS, Warburton VL, Dixen J & Davidson JM (1994). “Relationship among cardiovascular, muscular, and oxytocin responses during human sexual activity,” Archives of Sexual Behavior 23 59–79.

7. ^ Murphy ME, Seckl JR, Burton S, Checkley SA & Lightman SL (1987). “Changes in oxytocin and vasopressin secretion during sexual activity in men,” Journal of Clinical Endocrinology and Metabolism 65:738–741.

8. ^ Kruger THC, Haake P, Chereath D, Knapp W, Janssen OE, Exton MS, Schedlowski M & Hartmann U (2003). “Specificity of the neuroendocrine response to orgasm during sexual arousal in men,” Journal of Endocrinology 177:57–64

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10. ^ Jankowski et al. (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074-9 online PMID 15316117

11. ^ Walenty Hartwig – Practical Endocrinology, ISBN 83-200-1415-8

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13. ^ Vacek M, High on Fidelity. What can voles teach us about monogamy?

14. ^ Modahl C, Green L, Fein D et al. (1998). “Plasma oxytocin levels in autistic children”. Biol Psychiatry 43 (4): 270–7. doi:0.1016/S0006-3223(97)00439-3. PMID 9513736.

15. ^ Hollander E, Novotny S, Hanratty M et al. (2003). “Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders”. Neuropsychopharmacology 28 (1): 193–8. doi:10.1038/sj.npp.1300021. PMID 12496956.

16. ^ Hollander E, Bartz J, Chaplin W et al. (2007). “Oxytocin increases retention of social cognition in autism”. Biol Psychiatry 61 (4): 498–503. doi:10.1016/j.biopsych.2006.05.030. PMID 16904652.

17. ^ Kendrick KM, The Neurobiology of Social Bonds

18. ^ Kosfeld M et al. (2005) Oxytocin increases trust in humans. Nature 435:673-676. PDF PMID 15931222

19. ^ Kirsch P et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489-93 PMID 16339042

20. ^ Zak, P.J. Stanton, A.A., Ahmadi, A. 2007. Oxytocin increases generosity in humans. PLoS ONE 2(11): e1128. [3]

21. ^ Kovacs GL, Sarnyai Z, Szabo G. (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945-62 PMID 9924746

22. ^ Tyzio R et al.(2006) Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery. Science 314: 1788-1792 PMID 17170309

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24. ^ Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy”). Neuroscience. 146:509-14, 2007. PMID 17383105

25. ^ Fewtrell MS, Loh KL, Blake A, Ridout DA, Hawdon J. Randomised, double blind trial of oxytocin nasal spray in mothers expressing breast milk for preterm infants. Arch Dis Child Fetal Neonatal Ed. 2006 May;91(3):F169-74. PMID 16223754

26. ^ Boston Globe, January 12, 2006 [4]