CRH

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

CRH is produced in the hypothalamus, the first stage of the HPA axis, and plays an instrumental role in the regulation of the HPA axis and the human stress response.¹

• 1. Formation and inhibition of CRH
  • 1.1. Regions where CRH is formed
  • 1.2. What increases CRH formation
  • 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 by 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 a drug
  • 3.1. Applications 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 where 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 others, and is likely to enhance 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-enhancing) effects.³⁴

1.2. What increases CRH formation¶

• Stress
  • Stress functionally results in an increase in CRH⁵
    • In the central nucleus of the amygdala and
    • In the locus coeruleus
• Hypoglycemia (low blood sugar)
• Adrenalin⁶
• Norepinephrine⁶⁷
  • Reciprocal (mutual) neuronal connections exist between CRH and noradrenergic cells in the locus coeruleus. CRH and noradrenaline thereby stimulate each other, primarily by means of noradrenergic α1-receptors.⁸³
    This allows the HPA axis, autonomic nervous system, and cardiovascular system to interact to produce both short-term and sustained stress responses.
• Serotonin⁹⁷
• Acetylcholine⁷
• Histamine¹⁰
• Interleukin-1 (IL-1) of 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, by means of presynaptic CRH autoreceptors⁸

2. Effect of CRH¶

2.1. CRH receptors¶

CRH has a 30-fold greater affinity for CRH1 than for CRH2.¹²
Urocortin (UCN) has high affinity for CRH1 and CRH2¹²
UCN II and UCN III have high affinity for CRH2¹²

2.1.1. CRH1 receptor¶

CHR1 receptors mediate the rapid response of the fight-flight system controlled via CRH through 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 relevant in the brain rather than the body.¹²

Greatest 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 cholinergic forebrain neurons
    • Serotonergic neurons of the raphe nuclei
• Amygdala¹⁴¹
• Cerebellum¹⁴¹⁵
• Hippocampus¹⁴
• Olfactory bulb¹⁴
• Pituitary¹⁴
• Thalamus¹⁶
• Septum¹⁶
  • The CRH-1 receptor in the medial septum appears to mediate memory difficulties (stronger in male than in female rats).¹⁷ CRH at the CRH-1 receptor in the medial septum mediated retrieval but not recognition problems.
• Substantia nigra¹⁶
• Ventral tegmentum (VTA)¹⁶
• Nucleus striae terminalis¹
• Paraventricular hypothalamic nucleus (PVN)¹
• Nucleus accumbens¹⁸

Mice lacking the CRH1 receptor have less anxiety and less cognitive dysfunction in stressful situations. Drugs that inhibit this receptor are currently being tested.¹⁹²⁰

Differentially, a study in mice established that CRH via CRH1 receptors

• Triggers fear 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 amygdala and hippocampus.¹⁶
• In dopaminergic cells in the ventral tegmentum and substantia nigra stimulates dopamine release and thereby reduces anxiety.
  Artificial selective removal of these CRH1 receptors decreased 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 expectancy.²¹ Acute stress that increases CRH also increases dopamine, among others 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 - after up to 90 days after cessation of the stressor - the ability of CRH to increase dopamine in the nucleus accumbens and at the same time caused a switch from appetitive to aversive motivation,¹⁸ as is also observed in major depression MDD.²³

It is possible that an imbalance between glutamatergic and dopaminergic systems in relation to the action 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 has more of an anxiety inhibitory effect.¹³ The CRH2 receptor does not mediate depression or anxiety symptoms, but stress coping behaviors.²⁰ Unlike CRH1 receptors, cortisol does not inhibit CRH action at the CRH2 receptor.
In humans, CRH is thought to be relevant in the body rather than the brain.¹²

Greatest 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 nucleus of the solitary tract and area postrema.¹⁵

2.1.2.1. CRH2α receptor¶

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

• Heart
• Skeletal Musculature

2.1.2.3. CRH2-gamma receptor¶

Third isoform of the CRH2 receptor.¹²
Has been 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 adrenaline release in the adrenal medulla²⁸
• Dopamine synthesis²⁹
• Norepinephrine formation in the locus coeruleus³⁰⁵
  • Norepinephrine controls the stress responses of the brain (CNS).
  • For its part, norepinephrine activates the sympathetic nervous system and the HPA axis (positive feedback, reinforcement). Inhibition of this cascade occurs by GABA and glucocorticoids (cortisol).³¹³² Glucocorticoids inhibit CHR and norepinephrine production of 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 a reason for the frequent finding of elevated CRH levels with decreased cortisol levels.³³
  • Somatostatin inhibits the secretion of
    • Growth hormone
    • TRH and
    • Thyrotropin
      and thus suppresses reproductive, growth, and thyroid functions, all of which are controlled catecholaminergically.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, thereby contributing to the pathophysiology of AD. A use of CRH in the treatment of AD is discussed.³⁴

2.3. Behavioral effect of CRH¶

2.3.1. Behavioral triggering by CRH¶

CRH (directly injected) elicits immediate stress responses.³⁵ CRH antagonists block these responses.²⁷

• Attention
  • Sustained attention is impaired by CRH.³⁶
• Acoustic perception
• Memory problems
  • CRH in the medial septum (which projects to 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 decreased CRH levels. CRH1 receptors were equally expressed in both sexes. CRH1 antagonists prevented the memory problems caused by CRH.³⁷
• Wakefulness
• Locomotor activity (urge to move)⁵³⁸
• Caution in unknown environments, in the open field, in the elevated plus maze and in case of conflicts
• Exploration intensity in known environment³⁸
• Reduced exploration activity in new environment¹²
• Freezing behavior in unfamiliar environment³⁸
• Social withdrawal behavior (promotes social phobia)
• Fear¹²
  • Differentially, a study in mice established that CRH via CRHR1 receptors
    • Triggers fear 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 amygdala and hippocampus.¹⁶
    • In dopaminergic cells in the ventral tegmentum and substantia nigra stimulates dopamine release and thereby reduces anxiety.
      Artificial selective removal of these CRHR1 receptors decreased dopamine release in the PFC and increased anxiety.¹⁶
  • CRH mediates escape behavior and fear conditioning during unavoidable pain inflictions by activating serotonin release in the (caudal dorsal) raphe nuclei (DRN). CRH applied directly to the caudal DRN mediates these responses even without unavoidable pain infliction.³⁹ CRH in the rostral DRN did not elicit this.
• Startle response
• Fear Conditioning³⁹
  • Increased aversion to a stressor due to the fear experienced by that stressor⁴⁰
• Despair
• Negative mood⁴¹
• Increased thermogenesis via the catecholaminergic system³
• Increase energy metabolism and fat burning³⁴
• Increased heart rate and blood pressure¹²
• Stimulation/inhibition of gastrointestinal functions¹²
• Reduced sleep¹²
• Reduced food intake¹²

2.3.2. Behavioral inhibition by CRH¶

CRH decreased:

• 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 likewise when applied globally to the brain) dose-dependently reduces PFC performance (especially working memory). CRH antagonists abolish this effect.⁴²¹⁹
  Working memory is particularly impaired in ADHD.

2.3.3. CRH and mental disorders¶

CRH is elevated in¹

• Alzheimer
• Depression
• Anxiety disorders

2.4. Immunological effect of CRH¶

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

2.5. Neurotoxic effects of CRH in chronic stress¶

Prolonged high CRH levels lead to a reduced binding ability of CRH receptors in the PFC (downregulation).⁴³ Since the PFC is involved in inhibition of the HPA axis (stress axis), prolonged high cortisol levels lead to impaired inhibition of the HPA axis.⁴⁴

The effect of CRH may be enhanced by vasopressin on corticotroph hypohysial cells, especially during prolonged stress.⁴⁵
CRH output is co-regulated by higher-level entities, including the hippocampus.⁴⁵

3. CRH agonists and antagonists as a drug¶

3.1. Applications of CRH agonists¶

In the presence of a hypoactive HPA axis, usually identified by a flattened cortisostress response, fatigue, depressive symptomatology, hyperalgesia, and increased immune/inflammatory responses, CRH agonists could potentially be helpful. Areas of application could include

• Atypical depression³
• Bipolar disorder / manic-depressive disorder
  In our view, this follows from the fact that bipolar depression, like atypical depression, is characterized by a flattened endocrine stress response.
• Postpartum depression³
• Fibromyalgia³
• Chronic fatigue syndrome (fatigue)³
• ADHD-HI (with hyperactivity)
  In our view, this follows 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 presence of a hyperactive HPA axis, usually identified by an excessive cortisol stress response, CRH antagonists could possibly be helpful.

CRH antagonists include:

• 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 caused in primates exposed to social stress⁴⁶
    • Reduced anxiety / fear behavior
      • Body tremor
      • Grimace
      • Teeth grinding
      • Urinate
      • Bowel movement
    • Reinforced behavior that is suppressed when stressed
      • Explorative behavior
      • Sexual behaviors
    • Antalarmine (as well as CP-154,526) prevent ACTH increase on CRH¹²
      • Basal ACTH level
        • Unchanged after 1 week
        • Decreased after 11 days as well as after 8 weeks (corticosterone also decreased)
          • 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
    • Antalarmine inhibited ACTH response to conditioned fear and social stress but not to inescapable pain shocks¹²

• CP-154,526
  • Antalarmine 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 so to other stressors such as cold stress
  • CP-154,526 applied to the locus coeruleus inhibited norepinephrine response to handling stress but left norepinephrine, dopamine, and serotonin levels in the PFC unchanged

• Astressin¹²

  • CRH1 and CRH2 antagonist

• Antisauvagin-30 (AS-30)¹²

  • Over 300-fold selectivity for CRH2 over 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 by inhibition of CRH release

• Diazepam

  • Significantly and dose-dependently inhibited serotonin-induced CRH release, but 40 times more weakly than alprazolam⁴⁸

Areas of application could be for example

• Melancholic depression³
• Psychotic depression
• Chronic anxiety³
• ADHD-I
  In our view, this follows from the fact that ADHD-I is also characterized by an exaggerated endocrine stress response.
• SCT
  In our view, this follows 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 cerebrospinal fluid. This is not practical for usual 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 a dose-dependent manner in rats stressed by intense handling. The improvement was consistent with the degree of improvement produced by ADHD medications.⁴⁹ This was true for the nonselective CRH antagonist D-Phe-CRF as well as the selective CRH1 antagonist NBI 35965.