ACTH

ACTH is produced in the pituitary gland, the second stage of the HPA axis.
⇒ Pituitary gland (2nd stage): ACTH

• 1. Formation and inhibition of ACTH
  • 1.1. Increased ACTH production due to
    • 1.1.1. CRH
    • 1.1.2. Interleukin-2 (IL-2)
    • 1.1.3. Tumor necrosis factor (TNF)
    • 1.1.4. Vasopressin
    • 1.1.5. Delta(9)-tetrahydrocannabinol
    • 1.1.6. Adrenalin
    • 1.1.7. Noradrenaline
    • 1.1.8. Chronic inhibition of nitric oxide synthase
    • 1.1.9. Glucagon-like peptide 1 (GLP-1)
  • 1.2. Reduced ACTH production due to
    • 1.2.1. Cortisol (feedback loop)
    • 1.2.2. Oxytocin
    • 1.2.3. Alcoholism
• 2. Effect of ACTH
  • 2.1. Neuroendocrine effect of ACTH
  • 2.2. Behavioral effect of ACTH
• 3. Details about ACTH
• 4. Changes in ACTH due to chronic stress

1. Formation and inhibition of ACTH¶

1.1. Increased ACTH production due to¶

1.1.1. CRH¶

• Injected CRH causes¹
  • ACTH blood plasma response maximum after 15 minutes
  • Cortisol blood plasma maximum after 30 minutes
  • Cortisol saliva maximum after 45 minutes
• Injected CRH and vasopressin causes¹
  • ACTH blood plasma response maximum after 15 minutes
  • Cortisol blood plasma maximum after 45 minutes
  • Cortisol saliva maximum after 60 minutes

1.1.2. Interleukin-2 (IL-2)¶

Interleukin-2 from T lymphocytes increases the release of ACTH.²

1.1.3. Tumor necrosis factor (TNF)¶

Tumor necrosis factor (TNF) of macrophages increases the release of ACTH.²

1.1.4. Vasopressin¶

Vasopressin increases the release of ACTH.³

1.1.5. Delta(9)-tetrahydrocannabinol¶

Delta(9)-tetrahydrocannabinol increases the release of ACTH.³

1.1.6. Adrenalin¶

• Adrenalin⁴
  • Adrenaline from the adrenal medulla stimulates ACTH secretion by binding to α1-adrenergic receptors on corticotroph cells of the anterior pituitary gland⁵
  • Adrenaline stimulates CRF-induced cAMP accumulation, which acts as a “second messenger” of ACTH secretion⁵
  • Adrenaline stimulates ACTH more strongly than noradrenaline⁵
  • Adrenaline co-modulates the basal, peak and mean ACTH concentration and determines the level of the ACTH pulse amplitude alone⁶

1.1.7. Noradrenaline¶

Noradrenaline increases the release of ACTH⁵ (possibly only indirectly?).⁴

1.1.8. Chronic inhibition of nitric oxide synthase¶

Chronic inhibition of nitric oxide synthase increases the release of ACTH.

1.1.9. Glucagon-like peptide 1 (GLP-1)¶

Glucagon-like peptide 1 (GLP-1), injected into the medial paraventricular nucleus of the hypothalamus, increases ACTH, but not when injected into the amygdala.⁷

1.2. Reduced ACTH production due to¶

1.2.1. Cortisol (feedback loop)¶

• Cortisol inhibits the pituitary gland and thus the secretion of ACTH
• Negative feedback takes several hours⁵
• Cortisol causes inhibition of the transcription of pro-opiomelanocortin (POMC) by binding the glucocorticoid receptor-steroid complex to the DNA. Proteolytic cleavage of POMC reduces ACTH in the pituitary gland.⁵
• Desipramine reverses the negative feedback from cortisol into a positive one, while Resipin reverses the reversal in Cushing’s disease.⁸
• If cortisol is administered without daily rhythm fluctuations, this results in a reduced inhibition of ACTH secretion.⁹ This indicates that disturbances in the circadian system can trigger an excessive release of ACTH.
  According to our understanding, ADHD-HI and ADHD-C are often characterized by switch-off problems of the HPA axis.
• Long-term cortisone treatment causes a strong reduction or even cessation of ACTH production by the pituitary gland.¹⁰ We believe that this could be a long-term consequence of the unchecked release of ACTH by eliminating the daily cortisol rhythm.

1.2.2. Oxytocin¶

Oxytocin reduces the release of ACTH.
Blockade of oxytocin receptors in the brain by intracerebral administration of oxytocin antagonists into the paraventricluar nucleus of the hypothalamus increased HPA axis activity and basal ACTH and cortisol blood levels in rats, while stress-induced blood levels of ACTH and cortisol were reduced. Stress-induced anxiety behavior did not change. Administration of oxytocin antagonists into the medio-lateral septum did not induce basal ACTH changes, but reduced the stress-induced ACTH increase on emotional stress, but not on combined emotional and physical stress. Administration of oxytocin antagonists into the amygdala caused neither basal nor stress-induced changes in the HPA axis.¹¹¹²
In summary, this means that oxytocin downregulates the HPA axis by inhibiting the hypothalamus and pituitary gland and thereby

• Reduces the basal blood levels of ACTH and cortisol (which is typical of many mental disorders)
• As well as stress-induced blood levels of ACTH and cortisol (which is typical for externalizing mental disorders).

1.2.3. Alcoholism¶

Excessive alcohol consumption alters the HPA axis,¹³ whereby the changes already occur at the CRH and ACTH level of the HPA axis in the form of reduced hormone response levels.¹⁴

2. Effect of ACTH¶

2.1. Neuroendocrine effect of ACTH¶

• ACTH acts on the adrenal cortex
  • Promotion of
    • Cortisol production
    • DHEA production
• ACTH acts on the PFC
  • Increases the dimensional complexity of the EEG,¹⁵ which reduces the inhibition between competing active cell assemblies and thus produces a less focused perception
  • Reduces the negative difference wave (processing negativity) for different signals on the left and right ear,¹⁶ which leads to increased attention to irrelevant stimuli

2.2. Behavioral effect of ACTH¶

ACTH¹⁶

• Deteriorated
  • The selection of attention (paying attention to individual stimuli, ignoring others)
  • The focus of attention
  • Increases distractibility
• Leaves unchanged
  • Divided attention (observe all stimuli)

The reduction in attentional focus is triggered by intravenous and intranasal ACTH.
ACTH triggers a special processing mode of the cortex, which is characterized by a further distribution of resources in the processing of stimuli.¹⁵

ACTH impaired behavioral performance on convergent thinking tasks when presented orally. ACTH appears to reduce inhibitory control of the PFC, which is necessary for orderly analytical thinking.¹⁵

3. Details about ACTH¶

• In children with ADHD, no altered basal ACTH levels were found in any subtype.¹⁷¹⁸
• Augmentative (supportive) treatment with an ACTH 4-9 analog (Semax) for ADHD is discussed.¹⁹ Studies show that MPH (alone) shows significantly greater improvements than an ACTH 4-9 analog (alone).²⁰
• Chronic inhibition of nitric oxide synthase increases the ACTH response to exercise and decreases the ACTH response to the stressor of constraint/movement restriction. This indicates a stressor-specific modulation of ACTH by nitric oxide synthase.²¹
• Unlike cortisol (see Cortisol: details on cortisol), the plasma ACTH levels released in response to a stressor do not differ according to personality traits²²
  • In healthy adults, novelty seeking does not correlate with ACTH levels.²³
• Epilepsy is treated with ACTH administration²⁴
  • In a study in rats, ACTH administration at higher interictal peaks improved attention problems.²⁵
• Early experiences of stress can lead to disturbances in the ACTH receptor systems, which prevent the experience of anxiety from being extinguished and thus cause long-term stress. This can be improved by administering ACTH.²⁶ In our opinion, the change in the ACTH receptor systems could possibly be the result of a down/upregulation reaction. ⇒ Downregulation / upregulation
• SHR rats, considered an animal model of ADHD-HI, show increased ACTH and decreased basal cortisol levels.²⁷
• ACTH treatment promoted hyperactivity in some rats.²⁸

4. Changes in ACTH due to chronic stress¶

Chronic stress has an effect on ACTH:

• Increased ACTH in the pituitary gland²⁹³⁰³¹
• ACTH response to CRH increased³²³³
• Basal blood ACTH level unchanged³⁴³⁵³⁶

It should always be borne in mind that momentary reports as consequences of chronic stress can only represent a transitional stage of receptor down- or upregulation, depending on the duration of the stress exposure (see the phase model of stress development).