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Oxytocin is a neuropeptide from the group of proteohormones. As a neurohormone, neurotransmitter or neuromodulator, it is involved in a variety of central and peripheral effects, complex emotional and social human behavior, memory and learning processes.1

1. Formation of oxytocin

Oxytocin is produced in the hypothalamus (mainly in the paraventricular nucleus and to a lesser extent in the supraoptic nucleus) and stored in the pituitary gland until it is released.

Presumably, different cells of the hypothalamus are responsible for oxytocin in the brain and oxytocin in the body, whereby these two oxytocin levels appear to rise and fall symmetrically, so that the course of the blood oxytocin level also represents that of the brain.2

Iron deficiency can reduce oxytocin in the brain.3

2. Release of oxytocin

2.1. Neurophysiological mechanism

Oxytocin production is triggered as part of the stress response as a result of activation of the hypothalamus.

Noradrenaline and other neurotransmitters activate the hypothalamus as the first stage of the HPA axis, which then

  • Oxytocin and vasopressin are produced in the paraventricular nucleus and (to a lesser extent) in the supraoptic nucleus (in the hypothalamus)
    • Oxytocin and vasopressin (which is very similar to oxytocin) are (rapidly) transmitted by nerve axons to the pituitary gland, where they are initially stored in the posterior lobe of the pituitary gland and released into the blood as required
  • CRH and POMC, which activates the pituitary gland.

The pituitary gland

  • Releases oxytocin and vasopressin, which
    • Activate the autonomic nervous system
  • Releases ACTH
    • Which activates the adrenal gland (3rd stage of the HPA axis)

Cortisol also appears to trigger the release of oxytocin.4 As cortisol itself has an inhibitory effect on the hypothalamus, this oxytocin-stimulating effect must be mediated via other pathways.

Oestrogen is an oxytocin antagonist. This means that oestrogen indirectly increases the tend-and-befrind stress response, which could explain why this occurs much more frequently in women.5

2.2. Basal oxytocin level

A high basal oxytocin level correlates with

  • Anxiety in romantic relationships2
  • Social phobia6
  • Dissatisfaction with social ties6
  • Aggression in mothers (oxytocin in PVN and amygdala)7
  • Reduction of anxiety in men (oxytocin in PVN and amygdala)7

A low basal oxytocin level correlates with

  • Low functional autism.8 The stress response of cortisol, noradrenaline, adrenaline, oxytocin and vasopressin was unchanged.

2.3. Oxytocin stress response

Acute stress triggers an increased release of oxytocin. Within 1 to 15 minutes after an acute stressor, oxytocin levels increase 2.5-fold in healthy people.

In response to acute stress, the oxytocin level in adolescents rises very quickly to a maximum value within 1 minute and falls again after 10 minutes. The rise in oxytocin correlates with the rise in cortisol and the recovery of cortisol. A high oxytocin stress response correlates with high experienced anxiety and insecurity, while a high basal oxytocin level correlates with low experienced anxiety and insecurity.9

For both men and women, increased

  • Run for 10 minutes (running)
  • Sexual self-stimulation
  • Stress load (TSST)

within 10 to 15 minutes, the oxytocin level in saliva increases 2.5-fold.10
Sexual masturbation increases oxytocin levels in men and women, which are highest during orgasm.11

In contrast, a not insignificant number of studies found no oxytocin stress response to the TSST.

  • In women after the menopause, there was almost no increased oxytocin stress response.12 In one study, hormone therapy correlated with a higher oxytocin stress response. Oxytocin also showed no influence on stress reactivity or recovery after a stressor.
  • Young mothers also showed neither an increased oxytocin nor an increased allopregnanolone response to an acute stressor.13
  • In depressed women, no increased oxytocin levels were found in the blood 10 minutes after the TSST.14
    It is possible that the measurement was already outside the peak period after 10 minutes.
  • In young mothers, no change in oxytocin and vasopressin blood levels was observed as a stress response.15 The blood sample was taken 1 minute after the end of the stressor, i.e. at the expected maximum.

2.3.1. Oxytocin stress response differs according to attachment styles

One study found that basal oxytocin levels in children with ADHD were unchanged compared to those without ADHD. While oxytocin increased in non-affected children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase in ADHD sufferers after parent interaction to correspond to that of non-affected persons.16

People with early trauma may show specific stress responses of cortisol, ACTH and oxytocin depending on the attachment pattern.17

Against the background of our research findings that cortisol responses can differ depending on personality type, and in view of the realization that a strong oversupply or undersupply of neurotransmitters and hormones can cause a down- or upregulation of receptor systems, it is questionable whether the binding pattern-specific stress responses shown can be assigned in such a detailed, clear and stable manner.

Parents often pass on their own attachment patterns to their children. Mothers to 75%, fathers to 65%.18
Knowledge about the importance of attachment behavior could significantly reduce the rate of insecure attachments being passed on. Special courses are offered for this purpose.19

There are 4 different attachment styles in humans.
Attachment styles

2.3.2. “Measurement” of the oxytocin system by questionnaire on bonding

Cloninger20 suggested that the reward dependency scale of the Temperament and Character Inventory (TCI) reflects oxytocinergic function.
This scale correlates positively with self-reported secure attachment and emotionally warm parental attitudes and correlates negatively with rejecting/avoidant attachment and parental rejection.2122
The reward dependency scale has three subscales: sentimentality, dependency and attachment. The attachment subscale seems to best capture the behavior that correlates with oxytocin function. It measures the tendency to express feelings and share them with friends.17 This correlates with secure attachment.

2.3.3. Other factors for the oxytocin response

Breastfeeding women with postnatal depression showed

  • Lower oxytocin levels and higher cortisol levels during breastfeeding
  • Higher oxytocin levels and higher cortisol levels in response to a stressor (TSST)

than breastfeeding women without postpartum depression.23

Women only showed oxytocin responses to uncontrollable noise stress when their neuroticism score was high.24

A significantly lower oxytocin level was found in women with early childhood sexual abuse, correlating with the severity of the abuse.25

3. Degradation of oxytocin

Oxytocin has a blood half-life of approx. 6.5 to 7 minutes.26

4. Oxytocin and dopamine

Oxytocin activates dopaminergic reward pathways in response to social cues, inducing the rewarding quality of social interactions, which is relevant in ADHD, ASD, schizophrenia and addiction, among others.27

One review postulates that dopamine in particular regulates the incentive reward, (endogenous) opioids in particular the consummatory reward, while oxytocin moderates the orientation of the reward systems towards social interests. It is also assumed that positive experiences in early childhood increase incentive and consummatory reward sensitivity through the early activation of certain neuronal pathways.28

Oxytocin is involved in homeostatic, neuroadaptive processes associated with stress responses and substance use via interactions with the hypothalamic-pituitary-adrenal (HPA) axis and the mesolimbic reward-stress system of dopamine.1

Oxytocin and dopamine synergistically facilitate the activity of the striatum.2930 The activity of dopamine neurons in the ventral tegmentum and substantia nigra is finely regulated by axonal release of oxytocin.29

Rats that received oxytocin spent more time in a previously conditioned preferred location. If the rats were given the D2 DA receptor antagonist sulpiride before oxytocin, this blocked the rewarding oxytocin effect. The D2 antagonist alone did not affect the time the rats spent in the preferred location 31
Oxytocin also had an anxiolytic effect in the rats. Prior treatment with the D2 receptor antagonist sulpiride also blocked the anxiolytic effects of oxytocin.31

Parental support causes increased oxytocin levels in children32, which conveys a feeling of safety and security, which is described as secure attachment or a state of trust.33

Conversely, depression in the mother during the first years of the child’s life results in reduced oxytocin levels in the child, mother and father.32343536
Although oxytocin administration did not improve the parenting behavior of depressed mothers towards their children, it did improve their protective behavior towards aggressive third parties.32

Oxytocin in turn activates the reward system and increases the release of dopamine. Dopamine motivates future bonding behavior37 and plays a role (as a neurotrophic factor) in the conditioning process itself.38

Intracerebroventricularly administered oxytocin inhibited obesity-related conditioned appetite behavior in rats, possibly by reducing the phasic dopamine response in the ventral tegmentum to food stimuli.39

According to another study, local administration of oxytocin in the mPFC increased dopamine levels in the mPFC to the extent of oxytocin receptor activation, particularly via the D1 receptor. This indirectly activated the D1/PKA/DAPRR32 signaling pathway and induced antidepressant effects.40

The formation of qxytocin should also be stimulated by dopamine.41

HPC-1/Syntaxin1A (STX1A) -KO mice

HPC-1/Syntaxin1A (STX1A) is a neuronal soluble N-ethylmaleimide-sensitive fusion binding protein receptor that regulates the release of certain neurotransmitters in the brain. STX1A is associated with ASD and ADHD42. Mice lacking the STX1A receptor (STX1A KO - mice) have reduced oxytocin and dopamine levels and show neuropsychological abnormalities, such as anxiety memory deficits, increased impulsivity, unusual social behavior and increased anxiety during mild chronic stress. Oxytocin administration corrected these abnormalities 41
The impulsivity problems could be remedied by SSRIs, but not by dopamine or noradrenaline reuptake inhibitors 43
STX1A KO mice also show defects in the HPA axis with reduced basal corticosterone and ACTH levels and a reduced CRH, ACTH and corticosterone stress response. The increase in serotonin in the hypothalamus was reduced by the SSRI fluoxetine and by stress.44

5. Oxytocin receptor

So far, only one isoform of oxytocin receptors is known.45

In contrast, the hormones and neurotransmitters we have looked at in more detail so far, which are released at significantly different levels in response to stress (cortisol, noradrenaline), have a receptor system with different affinity receptors, in which the low-affinity receptors are only activated at very high levels and then pursue their own specific tasks (cortisol: deactivation of the HPA axis; noradrenaline: deactivation of the PFC).
Three receptors (1a, 1b and 2) have already been found for vasopressin, which is very closely related to oxytocin.45
Oxytocin receptors, on the other hand, appear to switch back and forth between a low-affinity and a high-affinity status.45 As with the cholecystokinin receptor, this is influenced by cholesterol, albeit in a different way.46

The oxytocin receptor requires at least two elements for high-affinity oxytocin binding:

  • Divalent cations such as Mn21 or Mg21 and
  • Cholesterol

Cholesterol thus acts agonistically as an oxytocin receptor modulator, possibly moderating the switch between low-affinity and high-affinity status.46 It is therefore assumed that high-affinity oxytocin receptors are primarily found in cholesterol-rich environments, e.g. in the cell membrane.
Cholesterol is also released in greater quantities under stress and increases blood pressure in the body with the aim of supplying the cells with more energy in the event of a fight or flight.
Depending on the genetic mutation of the oxytocin receptor genes, the affinity of the oxytocin receptor is reduced by a factor of up to 30 or increased by a factor of 20.45
As with vasopressin receptors, oxytocin receptor agonists can cause a significant downregulation of oxytocin receptors within 5 to 10 minutes. This can affect up to 60% of oxytocin receptors in certain cell types.45
In social phobia, a significantly reduced methylation of the oxytocin receptor gene was found, particularly in CpG Chr3: 8 809 437. The cortisol response to the TSST was increased, as was the amygdala responsiveness during a social phobia stressor.
It is assumed that reduced oxytocin receptor gene methylation causes increased oxytocin receptor expression. It remains to be seen whether the increased oxytocin receptor expression is a direct compensatory upregulation due to reduced oxytocin levels or a causal cause of social phobia.47
In prairie voles, a higher oxytocin receptor binding capacity correlates with maternal behavior.48

6. Effect of oxytocin

6.1. Regulatory areas of oxytocin

6.1.1. Behaviors

Oxytocin influences a wide range of behaviors and reactions.

  • Sexual behavior45
    • Strengthens commitment and monogamy49
  • Maternal behavior4549
  • Parental behavior37
  • Social behavior5051
    • Oxytocin given during a couple’s discussion52

      • Significantly increased positive communication behavior
      • Reduced the cortisol level after the conflict
    • Pair bonding51

    • Attachment styles51

      • The combination of oxytocin and certain attachment patterns could be linked to the female “Tend and be Friend” stress response175
    • Social interaction51

      • In postmenopausal women, increased oxytocin stress responses were significantly associated with lack of social relationships, fewer positive relationships with a primary partner, no pet, and increased cortisol stress responses, regardless of existing hormone therapy.12
  • Nutrition, care,45 parental care49
  • Memory and learning45
  • Tolerance and dependence on opioids45
  • Anxiolytic = anxiety-inhibiting, but this is modulated by the attachment pattern17
  • Stress-related behavior45
    • The combination of oxytocin and certain attachment patterns could be linked to the female “Tend and be Friend” stress response175

6.1.2. Effect on stress systems

Oxytocin influences stress-related behavior45

Oxytocin inhibits the HPA axis. Externally administered oxytocin thus reduces cortisol and ACTH levels.53545556

As a result, oxytocin reduces the fight, flight, freeze stress response.5
Oxytocin, on the other hand, increases the tend-and-befriend stress response.5
Oxytocin could possibly also have an inhibitory effect on CRH.5
As oestrogen increases oxytocin levels, all the effects of oxytocin are likely to be enhanced in women.
SSRIs increase the blood level of oxytocin. This may moderate some of the antidepressant effects of SSRIs.57

Oxytocin is involved in homeostatic, neuroadaptive processes associated with stress responses and substance use via interactions with the hypothalamic-pituitary-adrenal (HPA) axis and the mesolimbic reward-stress system of dopamine.1

6.2. Effect of oxytocin administration

Oxytocin administration in healthy people has the following effects

  • Increased positive social behavior58
  • Trust58
    • Oxytocin keeps trust high even when it has been violated several times, while the control group then lost their trust59
    • Oxytocin correlated with reduced activation of59
      • Amygdala, midbrain regions (which regulate anxiety)32
      • Dorsal striatum (which adapts behavior to social experiences)
  • Increases the willingness to take risks
    • Only in relation to social interaction58
    • Not against other risks58
  • Improves empathy60
  • Increases the observation of the eye region of other faces61
  • Activity of the amygdala
    • To frightening faces increased in women, decreased in men62
    • On (socially and non-socially) frightening movie scenes in women increased62

In marijuana addicts, oxytocin administration reduced

  • Craving for the drug
  • The DHEA level
  • The anxiety values
  • But not the subjective perception of stress in response to a stressor (TSST)63
    Accordingly, oxytocin could possibly be the treatment approach for atypical depression, ADHD-HI or other disorders characterized by a reduced cortisol-DHEA ratio. Further studies on this are desirable.

After learning 60 faces with happy, neutral or angry expressions, oxytocin or placebo was given nasally. Oxytocin improved memory recall for angry and neutral faces in both men and women, but not for friendly faces.64

Oxytocin or placebo was given before learning 36 happy, neutral or angry faces. The oxytocin recipients recognized more happy and neutral faces. Previously unlearned faces were not named more frequently as familiar.65

7. Oxytocin for ADHD

One study found that basal oxytocin levels in children with ADHD were unchanged compared to those without ADHD. While oxytocin increased in non-affected children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase in ADHD sufferers after parent interaction to correspond to that of non-affected persons.16

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