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CRH

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CRH

Corticotropin-releasing hormone

CRH triggers the pituitary gland to release the hormone ACTH

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Full HPA Axis Role

CRH (also called CRF — corticotropin-releasing factor) is a 41-amino-acid Neuropeptide and is the master initiator of the HPA (Hypothalamic–Pituitary–Adrenal) axis — the body’s central stress response system.


The HPA axis: CRH from the hypothalamus → ACTH from pituitary → cortisol from adrenal cortex → negative feedback to both hypothalamus and pituitary

HPA cascade:

  1. Stress (physical or psychological) → activates CRH neurons in the paraventricular nucleus (PVN) of the hypothalamus
  2. CRH → anterior pituitary (via hypophyseal portal blood) → stimulates ACTH (adrenocorticotropic hormone) release from corticotrophs
  3. ACTH → adrenal cortex → stimulates cortisol synthesis and release (within 15–30 minutes)
  4. Cortisol → negative feedback on both PVN (inhibits CRH) and pituitary (inhibits ACTH) → limits duration of the stress response

CRH neurons in the PVN also receive inputs from the amygdala, hippocampus (inhibitory via glucocorticoid receptors), brainstem, and higher cortical areas — allowing psychological stressors to activate the HPA axis even without physical threat.

CRH as Both Neuropeptide and Releasing Hormone

CRH is classified as both:

  • A releasing hormone (acts on pituitary via the portal system)
  • A neuropeptide with widespread actions in the brain independent of the HPA axis

CRH neurons and receptors are found throughout the CNS: amygdala, bed nucleus of the stria terminalis (BNST), locus coeruleus, hippocampus, prefrontal cortex, brainstem.

CRH Receptors: CRH-R1 and CRH-R2

ReceptorDistributionFunction
CRH-R1Pituitary, frontal cortex, amygdala, cerebellumHPA activation, anxiety-like behavior, stress response
CRH-R2Hypothalamus, brainstem, heart, skeletal muscleCardiovascular regulation, stress coping, appetite suppression

CRH-R1 mediates most of the anxiogenic (anxiety-promoting) effects of CRH.

Effects Beyond the HPA Axis

Central CRH (acting as a neuropeptide) has direct effects on behavior and physiology:

  • Anxiety and fear: CRH injected into the amygdala/BNST → anxiety-like behavior in animals; CRH-R1 antagonism reduces anxiety
  • Appetite suppression: CRH inhibits feeding (acts in hypothalamus and brainstem); counter to the cortisol-induced increase in appetite — acute stress suppresses appetite; chronic stress increases it
  • Arousal/wakefulness: CRH activates the locus coeruleus → norepinephrine release → alertness, reduced sleep
  • Immune modulation: CRH receptors on immune cells; CRH can be pro-inflammatory peripherally
  • Cognitive effects: Acute CRH → enhanced memory consolidation (adaptive for stress learning); chronic CRH → impaired hippocampal function

CRH Dysregulation in Psychiatric Disorders

Depression:

  • Elevated CRH in CSF and post-mortem brains of depressed patients
  • HPA hyperactivation (elevated cortisol, enlarged adrenal glands) — classic biological finding in melancholic depression
  • CRH-R1 knockout mice show antidepressant-like behavior

PTSD:

  • Paradoxically, PTSD often shows HPA hyporeactivity (low cortisol, high CRH) — possibly reflecting glucocorticoid receptor hypersensitivity and enhanced negative feedback
  • Elevated CRH in CSF of PTSD patients; correlates with symptom severity

CRH Antagonists as Experimental Antidepressants

CRH-R1 antagonists (e.g., pexacerfont, verucerfont) have been investigated as novel antidepressants and anxiolytics. They target the CRH signaling pathway rather than monoamines (serotonin/norepinephrine). Clinical trials have shown mixed results, but the approach remains active — particularly for stress-related depression and addiction (CRH drives relapse in animal models).

CRH and Vasopressin

Vasopressin (AVP) synergizes with CRH at the pituitary to amplify ACTH release. Under chronic stress, AVP co-secretion with CRH increases (via upregulation in PVN neurons), maintaining HPA activation even when CRH-R1 begins to desensitize. This AVP-mediated escape from negative feedback is thought to underlie chronic HPA hyperactivation in depression.

→ Einordnung: Neurotransmitter vs Neuropeptide vs Hormone · Hormone – Overview · Neuropeptide · Vasopressin

Erstellt: 03-09-22 13:56