ACTH

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

• 1. Formation and inhibition of ACTH
  • 1.1. Increased ACTH formation 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. Norepinephrine
    • 1.1.8. Chronic inhibition of nitric oxide synthase
    • 1.1.9. Glucagon-like peptide 1 (GLP-1)
  • 1.2. Reduced ACTH formation 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. ACTH details
• 4. Changes in ACTH due to chronic stress

1. Formation and inhibition of ACTH¶

1.1. Increased ACTH formation due to¶

1.1.1. CRH¶

• Injected CRH causes¹
  • ACTH blood plasma response maximum after 15 min
  • 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 min
  • 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 ACTH secretion.²

1.1.3. Tumor Necrosis Factor (TNF)¶

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

1.1.4. Vasopressin¶

Vasopressin increases ACTH secretion.³

1.1.5. Delta(9)-tetrahydrocannabinol¶

Delta(9)-tetrahydrocannabinol increases ACTH secretion.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 lobe⁵
  • 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 basal, peak, and mean ACTH concentrations and determines the level of ACTH pulse amplitude alone⁶

1.1.7. Norepinephrine¶

Norepinephrine increases ACTH secretion⁵ (possibly only indirectly?).⁴

1.1.8. Chronic inhibition of nitric oxide synthase¶

Chronic inhibition of nitric oxide synthase increases ACTH secretion.

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 formation due to¶

1.2.1. Cortisol (feedback loop)¶

• Cortisol inhibits the pituitary gland and thus the secretion of ACTH
• Negative feedback needs several hours⁵
• Cortisol causes inhibition of pro-opiomelanocortin (POMC) transcription by binding the glucocorticoid receptor-steroid complex to DNA. Proteolytic cleavage of POMC decreases ACTH in the pituitary gland.⁵
• Desipramine reverses the negative feedback by cortisol to a positive one, and Resipin reverses the reversal in Cushing’s disease.⁸
• If cortisol is given without diurnal rhythm fluctuations, this causes a reduced inhibition of ACTH release.⁹ This suggests that disturbances of the circadian system can trigger excessive ACTH release.
  In our understanding, ADHD-HI and ADHD-C are often characterized by shutdown problems of the HPA axis.
• Long-term cortisone treatment causes a strong reduction to cessation of ACTH production by the pituitary gland.¹⁰ According to our understanding, this could be a long-term consequence of unrestrained ACTH secretion by eliminating the diurnal cortisol rhythm.

1.2.2. Oxytocin¶

Oxytocin reduces ACTH release.
Blockade of brain oxytocin receptors by intracerebral administration of oxytocin antagonists to the paraventricular nucleus of the hypothalamus increased HPA axis activity and basal ACTH and cortisol blood levels in rats, whereas stress-induced blood levels of ACTH and cortisol were decreased. Stress-induced anxiety behavior did not change. Administration of oxytocin antagonists into the medio-lateral septum did not produce a basal ACTH change but decreased stress-induced ACTH elevation to emotional stress but not to combined emotional and physical stress. Administration of oxytocin antagonists to the amygdala did not produce basal or 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

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

1.2.3. Alcoholism¶

Excessive alcohol consumption alters the HPA axis,¹³ with changes already occurring at the CRH and ACTH levels of the HPA axis in the form of decreased 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 inhibition between competing active cell assemblies, producing less focused perception
  • Decreases the negative difference wave (processing negativity) for different signals on the left and right ear,¹⁶ which leads to an increased attention to irrelevant stimuli

2.2. Behavioral effect of ACTH¶

ACTH¹⁶

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

The reduction in attentional focus is induced by ACTH given intravenously as well as intranasally.
ACTH triggers a special processing mode of the cortex characterized by a further allocation 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 analytic thinking.¹⁵

3. ACTH details¶

• In children with ADHD, altered basal ACTH levels were not 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 higher 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 constraint/movement restriction. This suggests stressor-specific modulation of ACTH by nitric oxide synthase.²¹
• Unlike cortisol (see Cortisol: Details on Cortisol), plasma ACTH levels secreted in response to a stressor do not differ by 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 spikes improved attention problems.²⁵
• Early experiences of stress can result in disruptions of the ACTH receptor systems that prevent extinction of the fear experience, causing long-term stress. This can be ameliorated by ACTH administration.²⁶ In our opinion, the alteration of ACTH receptor systems could possibly be a consequence of a downregulation/upregulation response. ⇒ 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 causes in terms of ACTH:

• ACTH increased in the pituitary gland²⁹³⁰³¹
• ACTH response to CRH increased³²³³
• Basal blood ACTH levels unchanged³⁴³⁵³⁶

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