CRH

CRH, corticotropin releasing hormone, is also known as corticotropin releasing factor (CRF).

CRH is produced in the hypothalamus, the first stage of the HPA axis, and plays a key role in regulating the HPA axis and the human stress response.¹

• 1. Formation and inhibition of CRH
  • 1.1. Regions in which CRH is formed
  • 1.2. What increases CRH production
  • 1.3. What reduces CRH formation
• 2. Effect of CRH
  • 2.1. CRH receptors
    • 2.1.1. CRH1 receptor
    • 2.1.2. CRH2 receptor
      • 2.1.2.1. CRH2α receptor
      • 2.1.2.2. CRH2β receptor
      • 2.1.2.3. CRH2-gamma receptor
  • 2.2. Neurophysiological effects of CRH
    • 2.2.1. Activating effect of CRH
    • 2.2.2. Inhibitory effect of CRH
  • 2.3. Behavioral effect of CRH
    • 2.3.1. Behavioral triggering by CRH
    • 2.3.2. Behavioral inhibition due to CRH
    • 2.3.3. CRH and mental disorders
  • 2.4. Immunological effect of CRH
  • 2.5. Neurotoxic effects of CRH in chronic stress
• 3. CRH agonists and antagonists as medication
  • 3.1. Areas of application of CRH agonists
  • 3.2. Areas of application of CRH antagonists
• 4. Measurement of CRH
• 5. CRH and ADHD

1. Formation and inhibition of CRH¶

1.1. Regions in which CRH is formed¶

• In the paraventricular nucleus (PVN) of the hypothalamus (first stage of the HPA axis)
• CRH is also produced in the limbic system and the cortex, among other places, and is likely to reinforce the effect of CRH from the hypothalamus on the pituitary gland.²
• Furthermore, CRH is produced directly by peripheral nerves, where it is likely to have primarily immunological (inflammation-intensifying) effects.³⁴

1.2. What increases CRH production¶

• Stress
  • Stress results functionally in an increase in CRH⁵
    • In the central nucleus of the amygdala and
    • In the locus coeruleus
• Hypoglycemia (low blood sugar)
• Adrenalin⁶
• Noradrenaline⁶⁷
  • There are reciprocal (mutual) neuronal connections between CRH and noradrenergic cells in the locus coeruleus. CRH and noradrenaline thus stimulate each other, primarily via noradrenergic α1 receptors.⁸³
    This enables the interaction between the HPA axis, the autonomic nervous system and the cardiovascular system to generate both short-term and long-term stress reactions.
• Serotonin⁹⁷
• Acetylcholine⁷
• Histamine¹⁰
• Interleukin-1 (IL-1) of the monocytes¹¹
• Interleukin-6 (IL-6) of the monocytes¹¹

1.3. What reduces CRH formation¶

• Cortisol
  negative feedback loop - cortisol shuts down the HPA axis again
• GABA⁹ and its agonists, such as benzodiapines¹⁰
• CRH itself, via presynaptic CRH autoreceptors⁸

2. Effect of CRH¶

2.1. CRH receptors¶

CRH is 30 times more affine to CRH1 than to CRH2.¹²
Urocortin (UCN) has a high affinity for CRH1 and CRH2¹²
UCN II and UCN III have a high affinity for CRH2¹²

2.1.1. CRH1 receptor¶

CHR1 receptors mediate the CRH-controlled rapid response of the fight-flight system via the sympathetic nervous system and the HPA axis. CRH1 also activates the hypothalamic-pituitary-adrenal axis (HPA axis).¹³
In humans, CRH1 is thought to be more relevant in the brain than in the body.¹²

Highest density in

• Cortex¹⁴¹⁵
  • CRH neurons in the anterior cingulate cortex (ACC) receive information from¹
    • Cortex
    • Thalamus
    • Hippocampus
    • Amygdala
    • Several more midbrain and hindbrain nuclei
    • Basal forebrain cholinergic neurons
    • Serotonergic neurons of the raphe nuclei
• Amygdala¹⁴¹
• Cerebellum¹⁴¹⁵
• Hippocampus¹⁴
• Olfactory bulb¹⁴
• Pituitary gland¹⁴
• Thalamus¹⁶
• Septum¹⁶
  • The CRH-1 receptor in the medial septum appears to mediate memory difficulties (more so in male than in female rats).¹⁷ CRH at the CRH-1 receptor in the medial septum mediated problems in retrieval but not in object recognition.
• Substantia nigra¹⁶
• Ventral tegmentum (VTA)¹⁶
• Nucleus striae terminalis¹
• Paraventricular hypothalamic nucleus (PVN)¹
• Nucleus accumbens¹⁸

Mice without the CRH1 receptor have less anxiety and fewer cognitive disorders in stressful situations. Drugs that inhibit this receptor are currently being tested.¹⁹²⁰

In a differentiating study on mice, it was found that CRH via CRH1 receptors

• Triggers anxiety in glutamatergic systems of the forebrain and stimulates neurotransmission in the amygdala and hippocampus.
  Artificial selective removal of these CRH1 receptors reduced anxiety and inhibited neurotransmission in the amygdala and hippocampus.¹⁶
• Stimulates the release of dopamine in dopaminergic cells in the ventral tegmentum and the substantia nigra, thereby reducing anxiety.
  Artificial selective removal of these CRH1 receptors reduced dopamine release in the PFC and increased anxiety.¹⁶

CRH release in the nucleus accumbens appears to play a key role in potentiating motivation for reward anticipation.²¹ Acute stress that increases CRH also increases dopamine, including in the nucleus accumbens, which triggers motivational expectancy. A CRH1 antagonist blocks this reinforcing effect of acute stress on reward motivation.²² High chronic stress abolishes - up to 90 days after the stressor has ended - the ability of CRH to increase dopamine in the nucleus accumbens and at the same time causes a switch from appetitive to aversive motivation,¹⁸ as is also observed in major depressive disorder MDD.²³

It is possible that an imbalance between the glutamatergic and dopaminergic systems in relation to the effect of CRH contributes to the development of mental disorders.²⁴

Intradermal CRH injection induces a marked increase in vascular permeability and mast cell degranulation mediated by CRH type 1 receptors.²⁵

2.1.2. CRH2 receptor¶

The CRH2 receptor mediates the slower response of the stress system (adaptation and recovery). Urocortin II and urocortin III bind to CRH2.¹³ Urocortin is a neuropeptide related to CRH and binds much more strongly to CRH2 than CRH.¹⁴ It tends to have an anti-anxiety effect.¹³ The CRH2 receptor does not mediate symptoms of depression or anxiety, but stress scoping behavior.²⁰ Unlike CRH1 receptors, cortisol does not inhibit the CRH effect at the CRH2 receptor.
In humans, CRH is thought to be more relevant in the body than in the brain.¹²

Highest density in

• Hypothalamus¹⁴
• Lateral septum¹⁴¹⁵
• Hippocampus¹⁴
  • Ventral¹⁵
• Olfactory bulb¹⁵
• Bed nucleus of the stria terminalis¹⁵
• Ventromedial hypothalamic nucleus¹⁵
• Medial and posterior cortical nuclei of the amygdala¹⁵
• Mesencephalic raphe nuclei¹⁵
• And new localizations in the core of the solitary tract and area postrema.¹⁵

2.1.2.1. CRH2α receptor¶

In rats, the CRH2α receptor is not found in the brain.¹⁴

In humans, CRH2α is the predominant isoform. Found in both central and peripheral regions.
Mainly in subcortical brain regions:¹²

• Hypothalamus
• lateral septum
• Olfactory bulb

2.1.2.2. CRH2β receptor¶

In rats, the CRH2β receptor is only found in the brain, but not the CRH2α receptor.¹⁴
Primarily in¹²

• Heart
• Skeletal muscles

2.1.2.3. CRH2-gamma receptor¶

Third isoform of the CRH2 receptor.¹²
Found in the amygdala in humans.

2.2. Neurophysiological effects of CRH¶

2.2.1. Activating effect of CRH¶

CRH activates or promotes

• The (adeno-)pituitary gland (2nd stage of the HPA axis) by reducing the inhibitory potassium current²⁶
• The sympathetic nervous system (autonomic nervous system)²⁷ by triggering the release of adrenaline in the adrenal medulla²⁸
• Dopamine synthesis²⁹
• Noradrenaline production in the locus coeruleus³⁰⁵
  • Noradrenaline controls the stress reactions of the brain (CNS).
  • Noradrenaline in turn activates the sympathetic nervous system and the HPA axis (positive feedback, reinforcement). This cascade is inhibited by GABA and glucocorticoids (cortisol).³¹³² Glucocorticoids inhibit CHR and noradrenaline production in the nucleus coeruleus.³
• The release of somatostatin
  • Somatostatin in turn has an inhibitory effect on the HPA axis (negative feedback loop). This may be one reason for the frequent finding of elevated CRH levels with low cortisol levels.³³
  • Somatostatin inhibits the secretion of
    • Growth hormone
    • TRH and
    • Thyrotropin
      and thus suppresses the reproductive, growth and thyroid functions, all of which are controlled by catecholamines.³

2.2.2. Inhibitory effect of CRH¶

CRH inhibits the development of:

• GHRH³
• Glycogen synthase kinase 3β
  GSK-3β inactivates the protein glycogen synthase by phosphorylation and thereby contributes to the pathophysiology of Alzheimer’s disease. The use of CRH in the treatment of Alzheimer’s disease is discussed.³⁴

2.3. Behavioral effect of CRH¶

2.3.1. Behavioral triggering by CRH¶

CRH (injected directly) triggers immediate stress reactions.³⁵ CRH antagonists block these reactions.²⁷

• Attention
  • Sustained attention is impaired by CRH.³⁶
• Acoustic perception
• Memory problems
  • CRH in the medial septum (which projects into the hippocampus) caused memory problems in the hippocampus in both male and female rats. Males were more sensitive to CRH. Females had higher levels of CRH-binding protein, which reduced CRH levels. CRH1 receptors were equally strong in both sexes. CRH1 antagonists prevented the memory problems caused by CRH.³⁷
• Alertness
• Locomotor activity (urge to move)⁵³⁸
• Take care in unknown environments, in open spaces, in the elevated plus maze and in the event of conflicts
• Exploration intensity in a known environment³⁸
• Reduced exploration activity in a new environment¹²
• Freezing behavior in an unfamiliar environment³⁸
• Social withdrawal behavior (promotes social phobia)
• Fear¹²
  • A differentiating study in mice found that CRH via CRHR1 receptors
    • Triggers anxiety in glutamatergic systems of the forebrain and stimulates neurotransmission in the amygdala and hippocampus.
      Artificial selective removal of these CRH1 receptors reduced anxiety and inhibited neurotransmission in the amygdala and hippocampus.¹⁶
    • Stimulates the release of dopamine in dopaminergic cells in the ventral tegmentum and the substantia nigra, thereby reducing anxiety.
      Artificial selective removal of these CRHR1 receptors reduced dopamine release in the PFC and increased anxiety.¹⁶
  • CRH mediates escape behavior and fear conditioning in the presence of unavoidable pain by activating the release of serotonin in the (caudal dorsal) raphe nuclei (DRN). CRH, which is applied directly to the caudal DRN, mediates these reactions even without unavoidable inflictions of pain.³⁹ CRH in the rostral DRN did not trigger this.
• Startle reaction
• Fear conditioning³⁹
  • Increased aversion to a stressor due to the fear experienced as a result of it⁴⁰
• Despair
• Negative mood⁴¹
• Increased thermogenesis via the catecholaminergic system³
• Increase in energy turnover and fat burning³⁴
• Increased heart rate and blood pressure¹²
• Stimulation/inhibition of gastrointestinal functions¹²
• Reduced sleep¹²
• Reduced food intake¹²

2.3.2. Behavioral inhibition due to CRH¶

CRH reduced:

• Appetite via the catecholaminergic system³
• Libido
• Slow-wave sleep / deep sleep
• CRH (when applied directly to the dorsal mPFC, where a particularly large number of CRH receptors are located, and also when applied globally in the brain) reduces the performance of the PFC (especially working memory) in a dose-dependent manner. CRH antagonists neutralize this effect.⁴²¹⁹
  Working memory is particularly severely impaired in ADHD.

2.3.3. CRH and mental disorders¶

CRH is elevated in¹

• Alzheimer’s disease
• Depression
• Anxiety disorders

2.4. Immunological effect of CRH¶

• CRH secreted directly by the peripheral nerves stimulates local inflammation (immune CRH)³⁴
• CRH in the brain inhibits the inflammatory reaction via glucocorticoids (cortisol) and catecholamines.³
  This presumably means that CRH triggers a cortisol reaction. Cortisol is known to inhibit inflammation.

2.5. Neurotoxic effects of CRH in chronic stress¶

Prolonged high CRH levels lead to a reduced binding capacity of the CRH receptors in the PFC (downregulation).⁴³ As the PFC is involved in the inhibition of the HPA axis (stress axis), a long-lasting high cortisol level leads to an impairment of the inhibition of the HPA axis.⁴⁴

The effect of CRH can be enhanced by vasopressin on the corticotrophic hypohyseal cells, especially during prolonged stress.⁴⁵
CRH release is regulated by higher-level instances, including the hippocampus.⁴⁵

3. CRH agonists and antagonists as medication¶

3.1. Areas of application of CRH agonists¶

In the case of a hypoactive HPA axis, which can usually be identified by a flattened cortisostress response, fatigue, depressive symptomatology, hyperalgesia and increased immune / inflammatory reactions, CRH agonists could possibly be helpful. Areas of application could be, for example

• Atypical depression³
• Bipolar disorder / manic-depressive disorder
  In our opinion, this results from the fact that bipolar depression, like atypical depression, is characterized by a flattened endocrine stress response.
• Postpartum depression³
• Fibromyalgia³
• Chronic exhaustion syndrome (fatigue)³
• ADHD-HI (with hyperactivity)
  In our opinion, this results from the fact that ADHD-HI is also characterized by a flattened endocrine stress response.

3.2. Areas of application of CRH antagonists¶

In the case of a hyperactive HPA axis, which can usually be identified by an excessive cortisol stress response, CRH antagonists could possibly be helpful.

CRH antagonists are for example:

• Alpha-helical CRH (ah-CRH)¹²
• D-Phe CRH (d-Phe CRH)¹²
• Antalarmin (CP-156,181); similar to CP-154,526)
  • Selective CRH-1 antagonist¹²
  • 20 mg / kg in primates exposed to social stress caused⁴⁶
    • Reduced anxiety / fear behavior
      • Body tremors
      • Grimace
      • Teeth grinding
      • Urinating
      • Bowel movement
    • Reinforced behavior that is suppressed under stress
      • Explorative behavior
      • Sexual behavior
    • Antalarmin (also CP-154,526) prevent ACTH increase on CRH¹²
      • Basal ACTH level
        • Unchanged after 1 week
        • Reduced after 11 days as well as after 8 weeks (corticosterone also reduced)
          • Reduced responsiveness of the adrenal cortex to ACTH
          • No signs of adrenal insufficiency
        • ACTH and corticosterone response to immobilization stress unchanged
          • Response to acute stress remained intact
    • Antalarmin inhibited ACTH response to conditioned fear and social stress, but not to inescapable pain shocks¹²

• CP-154,526
  • Antalarmin analog
  • Selective CRH-1 antagonist¹²
  • Low oral bioavailability
  • High hepatic clearance
  • Drug development was stopped preclinically
  • CP-154,526 inhibited ACTH response to immobilization stress, but less to other stressors such as cold stress
  • CP-154,526 applied to the locus coeruleus inhibited noradrenaline response to handling stress, but left noradrenaline, dopamine and serotonin levels in the PFC unchanged

• Astressin¹²

  • CRH1 and CRH2 antagonist

• Antisauvagin-30 (AS-30)¹²

  • Over 300-fold selectivity for CRH2 compared to CRH1

• R121919 (NBI30775)⁴⁷

  • Selective CRH1 antagonist (Ki 2 - 5 nM)
  • CRH2 binding over 1000 times weaker

• SSR125543A

  • CRH1 antagonist

• Alprazolam

  • Significantly inhibited serotonin-induced CRH release in a dose-dependent manner⁴⁸
  • Probably due to inhibition of CRH secretion

• Diazepam

  • Significantly inhibited serotonin-induced CRH release in a dose-dependent manner, but 40 times weaker than alprazolam⁴⁸

Areas of application could be, for example

• Melancholic depression³
• Psychotic depression
• Chronic anxiety³
• ADHD-I
  In our opinion, this results from the fact that ADHD-I is also characterized by an excessive endocrine stress response.
• SCT
  In our opinion, this results from the fact that SCT is most likely also characterized by a flattened endocrine stress response.

4. Measurement of CRH¶

CRH in the brain can only be measured in the cerebrospinal fluid. This is not practical for standard diagnostics or treatment.
CRH can also be measured in blood plasma.

5. CRH and ADHD¶

One study found that CRH1 antagonists were able to improve working memory in rats stressed by intensive handling in a dose-dependent manner. The improvement corresponded to the degree of improvement with ADHD medication.⁴⁹ This applied to the non-selective CRH antagonist D-Phe-CRF as well as the selective CRH1 antagonist NBI 35965.