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Oxytocin

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Oxytocin

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

1. Oxytocin formation

Oxytocin is produced in the hypothalamus (there mainly in the nucleus paraventricularis and to a lesser extent in the nucleus supraopticus) and stored in the pituitary gland until release.

Presumably, different cells of the hypothalamus are responsible for oxytocin in the brain and oxytocin in the body, and these two oxytocin levels seem 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. Oxytocin release

2.1. Neurophysiological mechanism

Oxytocin production is triggered during the stress response as a consequence of hypothalamic activation.

Norepinephrine and other messengers activate the hypothalamus as the first stage of the HPA axis, which then

  • In the nucleus paraventricularis and (to a lesser extent) in the nucleus supraopticus (in the hypothalamus) produces oxytocin and vasopressin
    • Oxytocin and vasopressin (which is very similar to oxytocin) are mediated by nerve axons (fast) to the pituitary gland (hypophysis) where they are first stored in the posterior pituitary lobe and from there released into the blood as needed
  • CRH and POMC release, which activates the pituitary gland.

The pituitary gland

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

Cortisol also appears to trigger oxytocin release.4 Since cortisol in itself has an inhibitory effect on the hypothalamus, this oxytocin-stimulating effect would have to be mediated by other pathways.

Estrogen is an oxytocin antagonist. Thus, estrogen indirectly enhances the tend-and-befrind stress response, which may explain why it occurs much more frequently in women.5

2.2. Basal oxytocin level

A high basal oxytocin level correlates with

  • Anxiety in romantic attachments2
  • Social phobia6
  • Dissatisfaction with social ties6
  • Aggression in mothers (oxytocin in PVN and amygdala)7
  • Anxiety reduction in men (oxytocin in PVN and amygdala)7

A low basal level of oxytocin correlates with

  • Low-functioning autism.8 The stress response of cortisol, norepinephrine, epinephrine, 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 individuals.

In response to acute stress, oxytocin levels in adolescents rise very rapidly to a maximum level within 1 minute and drop again after only 10 minutes. The oxytocin rise correlates with the cortisol rise and cortisol recovery. A high oxytocin stress response correlates with high experienced anxiety and insecurity, whereas a high basal oxytocin level correlates with low experienced anxiety and insecurity.9

For both men and women, increased

  • Run for 10 minutes (running sport)
  • Sexual self-stimulation
  • Stress Stress (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.

  • Postmenopausal women showed almost no increased oxytocin stress response.12 Hormone therapy correlated with a higher oxytocin stress response in one study. 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 blood oxytocin level was found 10 minutes after TSST.14
    Possibly the measurement was already outside the peak period after 10 minutes.
  • In young mothers, no change in oxytocin and vasopressin blood levels was detected as a stress response.15 Blood sampling was performed 1 minute after the end of the stressor, i.e., at the expected maximum.

2.3.1. Oxytocin stress response differs by attachment styles

One study found basal oxytocin levels unchanged in children with ADHD compared to unaffected individuals. While oxytocin increased in unaffected children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase after parent interaction in ADHD sufferers to match that of nonaffected individuals.16

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

In light of our research findings that cortisol responses may differ by personality type, and in light of the recognition that a severe oversupply or undersupply of neurotransmitters and hormones may cause downregulation or upregulation of receptor systems, it is questionable whether the presented binding pattern-specific stress responses can be assigned in such a detailed, unambiguous, and stable manner.

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

A distinction is made between 4 attachment styles in people.
Attachment Styles

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

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 parent attitudes and correlates negatively with dismissive/avoidant attachment and parent 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 oxytocin response factors

Breastfeeding women with postnatal depression showed

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

than breastfeeding women without postpartum depression.23

Oxytocin responses to uncontrollable noise stress were shown by women only when neuroticism was also high.24

Significantly lower oxytocin levels were found in women with early childhood sexual abuse, correlating with the severity of the abuse.25

3. Oxytocin degradation

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

4. Oxytocin and dopamine

Oxytocin activates dopaminergic reward pathways in response to social cues, thereby 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 incentive reward, (endogenous) opioids in particular regulate consummatory reward, whereas oxytocin moderates the alignment of reward systems with social interests. Further, it is hypothesized that early childhood positive experiences increase incentive and consummatory reward sensitivity through early activation of specific neural 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 dopamine mesolimbic reward-stress system.1

Oxytocin and dopamine synergistically facilitate striatal activity.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 at a previously conditioned preferred location. If the rats received the D2 DA receptor antagonist sulpiride before the oxytocin, this blocked the rewarding oxytocin effect. The D2 antagonist alone did not affect the time rats spent at the preferred location.31
Oxytocin also had anxiolytic effects in the rats. Prior treatment with the D2 receptor antagonist sulpiride also blocked the anxiolytic effects of oxytocin.31

Parental support causes increased levels of oxytocin in children32, which provides a sense 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 causes decreased levels of oxytocin in the child, mother, and father.32343536
Oxytocin administration did not improve depressed mother’s parenting behavior toward children, but it did improve protective behavior from aggressive third parties.32

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

Intracerebroventricularly given oxytocin inhibited obesity-related conditioned appetitive 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 caused increased levels of dopamine in the mPFC to the extent of oxytocin receptor activation, particularly by means of the D1 receptor. This indirectly activated the D1/PKA/DAPRR32 pathway and produced antidepressant effects.40

The formation of qxytocin is further thought to 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 decreased oxytocin and dopamine levels and exhibit neuropsychological abnormalities, such as fear memory deficits, increased impulsivity, unusual social behavior, and increased anxiety in mild chronic stress. Oxytocin administration corrected these abnormalities.41
The impulsivity problems could be resolved with SSRIs, but not with dopamine or norepinephrine reuptake inhibitors.43
STX1A KO - Mice also show defects of the HPA axis with decreased basal corticosterone and ACTH levels and decreased CRH, ACTH, and corticosterone stress response. The increase in serotonin in the hypothalamus by the SSRI fluoxetine as well as by stress was decreased.44

5. Oxytocin receptor

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

In contrast, the hormones and neurotransmitters that we have looked at in more detail so far, which are released at significantly different levels depending on stress (cortisol, norepinephrine), have a receptor system of different affinity receptors, in which the low-affinity receptors are only addressed at very high levels and then pursue specific tasks of their own (cortisol: shutdown of the HPA axis; norepinephrine: shutdown of the PFC).
In the case of vasopressin, which is very closely related to oxytocin, three receptors (1a, 1b and 2) have already been found.45
Oxytocin receptors, on the other hand, appear to alternate 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

For high-affinity oxytocin binding, the oxytocin receptor requires at least two elements:

  • Divalent cations such as Mn21 or Mg21 and
  • Cholesterol

Cholesterol thus acts agonistically as an oxytocin receptor modulator, possibly moderating the switch between low. and high-affinity status.46 Therefore, it is suspected that high-affinity oxytocin receptors are likely to be found predominantly in cholesterol-rich environments, e.g. in the cell membrane.
Cholesterol is also released more when stressed and increases blood pressure in the body with the goal of providing cells with more energy in case of fight or flight.
Depending on the genetic mutation of the oxytocin receptor genes, the affinity of the oxytocin receptor is reduced by up to 30-fold or increased by 20-fold.45
As with vasopressin receptors, oxytocin receptor agonists can cause significant downregulation of oxytocin receptors within 5 to 10 minutes. This can affect up to over 60% of oxytocin receptors in certain cell types.45
In social phobia, significantly decreased methylation of the oxytocin receptor gene is evident particularly at CpG Chr3: 8 809 437, where the cortisol response to the TSST was increased as was amygdala responsiveness during a social phobia stressor.
Decreased oxytocin receptor gene methylation is thought to cause increased oxytocin receptor expression. It is open whether the increased oxytocin receptor expression represents a direct compensatory upregulation due to decreased oxytocin levels or is a causal cause of social phobia.47
In prairie voles, higher oxytocin receptor binding ability 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 responses.

  • Sexual behavior45
    • Strengthens bond and monogamy49
  • Maternal behavior4549
  • Parenting Behavior37
  • Social behavior5051
    • Oxytocin given during a couple conflict discussion52

      • Significantly increased positive communication behavior
      • Reduced the level of cortisol after the conflict
    • Pair bond51

    • Attachment Styles (Attachment)51

      • The combination of oxytocin and certain attachment patterns may be related to the female “tend and be friend” stress response175
    • Social interaction51

      • In postmenopausal women, regardless of existing hormone therapy, 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.12
  • Nutrition, care,45 parental care49
  • Memory and learning45
  • Tolerance and dependence on opioids45
  • Anxiolytic = Anxiety inhibitory, but this is modulated by the attachment pattern17
  • Stress-related behavior45
    • The combination of oxytocin and certain attachment patterns may be related 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 given oxytocin thus reduces cortisol and ACTH levels.53545556

Thus, oxytocin reduces the fight, flight, freeze stress response.5
Oxytocin, on the other hand, enhances the tend-and-befriend stress response.5
Oxytocin could possibly also have an inhibitory effect on CRH.5
Since estrogen increases oxytocin levels, all effects of oxytocin are likely to be enhanced in women.
SSRIs increase blood levels of oxytocin. It is possible that this moderates 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 dopamine mesolimbic reward-stress system.1

6.2. Effect of oxytocin administration

Oxytocin administration in healthy people causes

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

In marijuana abusers, oxytocin administration reduced

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

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. Oxytocin recipients recognized more happy and neutral faces. Previously unlearned faces were not named more often as familiar.65

7. Oxytocin in ADHD

One study found basal oxytocin levels unchanged in children with ADHD compared to unaffected individuals. While oxytocin increased in unaffected children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase after parent interaction in ADHD sufferers to match that of nonaffected individuals.16


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