Oxytocin

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
• 2. Release of oxytocin
  • 2.1. Neurophysiological mechanism
  • 2.2. Basal oxytocin level
  • 2.3. Oxytocin stress response
    • 2.3.1. Oxytocin stress response differs according to attachment styles
    • 2.3.2. “Measurement” of the oxytocin system by questionnaire on bonding
    • 2.3.3. Other factors for the oxytocin response
• 3. Degradation of oxytocin
• 4. Oxytocin receptor
• 5. What influences oxytocin
• 6. Effect of oxytocin
  • 6.1. Regulatory areas of oxytocin
    • 6.1.1. Behaviors
    • 6.1.2. Effect on stress systems
    • 6.1.3. Gender-dependent effect of oxytocin
  • 6.2. Effect of oxytocin administration
• 7. Oxytocin and dopamine
• 8. Oxytocin for ADHD
• 9. Oxytocin for ASS

1. Formation of oxytocin¶

Oxytocin is produced in the brain 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.
In addition, oxytocin can be released from the dendrites of the parvocellular as well as the magnocellular neurons in the PVN and SON.²

Oxytocin as a hormone is released peripherally from the neurohypophysis into the bloodstream. Only small amounts of oxytocin cross the blood-brain barrier²

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.³ A social defeat, on the other hand, led to an increase in oxytocin in certain areas of the brain, while it remained unchanged in the peripheral blood.⁴

Iron deficiency can reduce oxytocin in the brain.⁵

2. Release of oxytocin¶

2.1. Neurophysiological mechanism¶

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

Noradrenaline and other messenger substances activate the hypothalamus as the first increment 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 increment of the HPA axis)

Cortisol also appears to trigger the release of oxytocin.⁶ As cortisol itself has an inhibitory effect on the hypothalamus, this oxytocin-stimulating effect must be mediated via other pathways.

Stimulation of the vagus nerve causes a release of oxytocin.²

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.⁷

2.2. Basal oxytocin level¶

A high basal oxytocin level correlates with

• Anxiety in romantic relationships³
• Social phobia⁸
• Dissatisfaction with social ties⁸
• Aggression in mothers (oxytocin in PVN and amygdala)⁹
• Reduction of anxiety in men (oxytocin in PVN and amygdala)⁹

A low basal oxytocin level correlates with

• Low functional autism.¹⁰ 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 of 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.¹¹

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.¹²
Sexual masturbation increases oxytocin levels in men and women, which are highest during orgasm.¹³

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.¹⁴ 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.¹⁵
• In depressed women, no increased oxytocin levels were found in the blood 10 minutes after the TSST.¹⁶
  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.¹⁷ 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 the disorder. While oxytocin increased in non-affected people after interaction with a parent, oxytocin decreased in untreated people with ADHD. Methylphenidate caused the oxytocin increase in persons with ADHD after parent interaction to correspond to that of non-affected people.¹⁸

People with early trauma may show specific stress responses of cortisol, ACTH and oxytocin depending on the attachment pattern.¹⁹

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

Cloninger²² 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.²³²⁴
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.¹⁹ 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.²⁵

Women only showed oxytocin responses to uncontrollable noise stress when their neuroticism score was high.²⁶

A significantly lower oxytocin level was found in women with early childhood sexual abuse, correlating with the severity of the abuse.²⁷

3. Degradation of oxytocin¶

Oxytocin has a blood half-life of approx. 6.5 to 7 minutes.²⁸

4. Oxytocin receptor¶

So far, only one isoform of oxytocin receptors is known.²⁹

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.³⁰ 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 20.²⁹
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.²⁹
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.³¹
In prairie voles, a higher oxytocin receptor binding ability correlates with maternal behavior.³²

5. What influences oxytocin¶

Oxytocin is increased by:

• SSRI³³³⁴
• 5HT agonists³⁵
  • 5-HT1A receptor agonists (5 to 8 times more potent than 5-HT2A C receptor agonists)
  • 5-HT2A/C receptor agonists
  • not by 5-HT2B or 5-HT3 receptor agonists

Oxytocin is reduced in

• ADHD (see below)
• ASS (see below)
• PTSD³⁶
• Depression³⁷
  • even stronger than with PTSD

Oxytocin is elevated in

• Obsessive-compulsive disorder³⁷

6. Effect of oxytocin¶

6.1. Regulatory areas of oxytocin¶

6.1.1. Behaviors¶

Oxytocin influences a wide range of behaviors and reactions.

• Sexual behavior²⁹
  • Strengthens commitment and monogamy³⁸
• Maternal behavior²⁹³⁸
• Parental behavior³⁹
• Social behavior⁴⁰⁴¹
  • Oxytocin and oxytocin receptor knockout mice may not even recognize other mice.²
  • Oxytocin given during a couple’s discussion⁴²
    • Significantly increased positive communication behavior
    • Reduced the cortisol level after the conflict
  • Pair bonding⁴¹
  • Attachment styles⁴¹
    • The combination of oxytocin and certain attachment patterns could be linked to the female “Tend and be Friend” stress response¹⁹⁷
  • Social interaction⁴¹
    • 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.¹⁴
• Nutrition, care,²⁹ parental care³⁸
• Memory and learning²⁹
• Tolerance and dependence on opioids²⁹
• Anxiolytic = anxiety-inhibiting, but this is modulated by the attachment pattern¹⁹
• Stress-related behavior²⁹
  • The combination of oxytocin and certain attachment patterns could be linked to the female “Tend and be Friend” stress response¹⁹⁷

6.1.2. Effect on stress systems¶

Oxytocin influences stress-related behavior²⁹

Oxytocin inhibits the HPA axis. Externally administered oxytocin thus reduces cortisol and ACTH levels.^43444546

As a result, oxytocin reduces the fight, flight, freeze stress response.⁷
Oxytocin, on the other hand, increases the tend-and-befriend stress response.⁷
Oxytocin could possibly also have an inhibitory effect on CRH.⁷
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.⁴⁷

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

6.1.3. Gender-dependent effect of oxytocin¶

Women have higher oxytocin levels than men.³⁷

Oxytocin shows a gender-dependent difference in the activation of brain regions that process social stimuli, particularly the amygdala. In addition, depending on the context, oxytocin appears to promote social cognition and positive social interactions more frequently in men than in women.⁴⁸⁴⁹

6.2. Effect of oxytocin administration¶

Oxytocin administration in healthy people has the following effects

• Increased positive social behavior⁵⁰
• Trust⁵⁰
  • Oxytocin keeps trust high even when it has been violated several times, while the control group then lost their trust⁵¹
  • Oxytocin correlated with reduced activation of⁵¹
    • Amygdala, midbrain regions (which regulate anxiety)⁵²
    • Dorsal striatum (which adapts behavior to social experiences)
• Increases the willingness to take risks
  • Only in relation to social interaction⁵⁰
  • Not against other risks⁵⁰
• Improves empathy⁵³
• Increases the observation of the eye region of other faces⁵⁴
• Activity of the amygdala
  • To frightening faces increased in women, decreased in men⁵⁵
  • On (socially and non-socially) frightening movie scenes in women increased⁵⁵

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)⁵⁶
  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.⁵⁷

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.⁵⁸

7. Oxytocin and dopamine¶

Oxytocin neurons project to many areas with dopaminergic neurons or that are reached by dopaminergic neurons, such as²

• VTA
• Striatum
• Hippocampus
• Amygdala
• Nucleus accumbens
• PFC
• Olfactory bulb
• Brain stem
• Spinal cord

Oxytocin increases dopamine levels in, among others:²

• medial preoptic area
• Amygdala
• VTA

Oxytocin receptors are also located here.

Activation of oxytocin neurons in the VTA increases dopaminergic activity in the mesocorticolimbic system. Mice showed a decrease in dopaminergic release in the nucleus accumbens after administration of an oxytocin receptor agonist.⁵⁹ An intracerebroventricularly administered oxytocin antagonist decreases the release of dopamine in response to a dopamine agonist.⁶⁰

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.⁶¹

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.⁶²

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.⁶³⁶⁴ The activity of dopamine neurons in the ventral tegmentum and substantia nigra is finely regulated by axonal release of oxytocin.⁶³

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 ⁶⁵
Oxytocin also had an anxiolytic effect in the rats. Prior treatment with the D2 receptor antagonist sulpiride also blocked the anxiolytic effects of oxytocin.⁶⁵

Parental support causes increased oxytocin levels in children⁵², which conveys a feeling of safety and security, which is described as secure attachment or a state of trust.⁶⁶
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.^52676869
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.⁵²

Oxytocin in turn activates the reward system and increases the release of dopamine. Dopamine motivates future bonding behavior³⁹ and plays a role (as a neurotrophic factor) in the conditioning process itself.⁷⁰

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.⁷¹

Both oxytocin and dopamine increase in response to sexual arousal and sexual activity²
Sexual behavior releases oxytocin in the amygdala and the nucleus accumbens.⁷²
An oxytocin-dopamine cycle was assumed for this purpose:⁷³

• the release of oxytocin in the amygdala, the hippocampus and the VTA stimulate the mesolimbic dopamine system
• the activated mesolimbic dopamine system then stimulates the incertohypothalamic dopaminergic fibers
• the activated incertohypothalamic dopaminergic fibers innervate the medial preoptic area, the PVN and the SON
• which leads to a further release of oxytocin
• which in turn activates the “rewarding” mesolimbic dopaminergic pathways

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.⁷⁴
Dopamine, in turn, is said to stimulate oxytocin synthesis.⁷⁵

Oxytocin and dopamine D2 receptors form receptor heterodimers in the nucleus accumbens and amygdala.⁷⁹

.²

In young adults with ASD, oxytocin led to an improvement in learning ability and increased signal transmission in the nucleus accumbens.⁸⁰

8. Oxytocin for ADHD¶

One study found reduced oxytocin levels in children with ADHD⁸¹
Another study found that basal oxytocin levels in children with ADHD were unchanged compared to unaffected children. While oxytocin increased in non-affected people after interaction with a parent, oxytocin decreased in untreated people with ADHD. Methylphenidate caused the oxytocin increase in persons with ADHD after parental interaction to correspond to that of non-affected people¹⁸
In adults, no correlation was found between ADHD and oxytocin levels.⁸²

SHR, the main ADHD animal model, shows decreased oxytocin levels.⁸³

Rats pretreated with oxytocin showed a significantly greater increase in dopamine to MPH. An oxytocin antagonist suppressed this response. ⁸⁴

Prenatal oxytocin exposure does not appear to affect ADHD and ASD risk.⁸⁵

9. Oxytocin for ASS¶

Children (but not adolescents) with ASD showed reduced oxytocin levels. In some (but not all) studies, oxytocin improved social behavior and repetitive behavior.²

Oxytocin is said to play a role in ASD and anxiety.⁸⁶
ASA correlated with certain oxytocin receptor polymorphisms.²

A mouse model of autism that receives oxytocin within 5 minutes of birth shows normalized social recognition in the long term.^87888990
Rats that received oxytocin after birth showed long-lasting behavioral changes.⁹¹⁹²

The Shank3B-KO mouse, an ASA animal model showing reduced oxytocin immunoreactivity in the PVN, elicited oxytocin:⁹³

• stronger social behavior
  • only if the oxytocin receptors in dopaminergic neurons have been blocked
• increased dopaminergic activity in the VTA