L2 HPA axis Flashcards
The hypothalamus contains the _______ ______ (PVN) which contains _____ ______ hormone (CRH) neurones. The hypothalamus releases CRH which acts on the _____ _____. The _____ _____ produces __________ ______ (_ _ _ _) which acts on adrenal glands to produce ______. _____ liberates energy and glucose stores to prepare for fight/flight.
Paraventricular nucleus Corticotrophin releasing hormone (CRH) Pituitary gland Pituitary gland Adrenocorticotrophic hormone (ACTH) Cortisol Cortisol
So…
Stress causes ______ to release _ _ _ which acts on the ______ which releases _ _ _ _ which acts on the _______ ______ to produce ______ which binds _________ receptors and ________ receptors which then has a negative feedback.
Hypothalamus CRH Pituitary ACTH Adrenal glands Cortisol Mineralocorticoid and glucocorticoid
Cortisol has physiological effects e.g.
1) Anti _____ and auto ____ effects which puts a brake on the immune system
2) Actions on reactivity to _____ in blood e.g. effects on arterioles and BP
3) Maintains concentrations of _____ involved in metabolic homeostasis
4) Enhances ______ permeability
5) ______ proteins to fat to provide energy
6) Inhibits _____ and r_______
7) Catabolism of cells of immune system, bone, muscles to provide substrates for _______________.
Hence chronic exposure to stress = reduction in bone density, immune func and reproductive fertility
1) Anti inflammatory and autoimmune
2) Adrenaline
3) Enzymes
4) Vascular
5) Catabolises
6) growth and reproduction
7) Gluconeogenesis
HPA axis has a role in anxiety and depression:
- Elevated cortisol is a feature of MDD and psychotic depression
- In healthy individuals there is a _____ feedback in HPA axis to _____ the amount of ____ produced but in chronic stress and MDD this is switched off and cortisol levels are unregulated.
- This is demonstrated by the _______ _______ test.
Negative
Reduce
Cortisol
Dexamethasone suppression
Successful depression treatment with ____ restores the HPA axis ______ feedback
SSRIs
Negative
Cortisol acts as a _____ feedback regulator of HPA axis at several levels:
- Reduces ____ and _____
- Does this by switching off _____ ____ and ______.
Negative CRH ACTH Anterior pituitary Hypothalamus
The _____ _____ test can test for dysregulation of the HPA axis. No suppression of _____ secretion in test is a biomarker for depression. Give dexamethasone around 11pm and test cortisol in morning around 8am - measure and if reduced cortisol then _____ successful.
Dexamethasone suppression
Cortisol
Treatment
How does cortisol negative feedback work?
1) Cortisol acts on _____ _____ ______ receptors in ________ and _____ _____.
2) Cortisol binding to the __ causes it to ______ to the nucleus
3) This activates _____ _____ by binding _______ _______ ______ (GREs) in genes
4) These TFs repress gene expression so leads to reduced ____
5) Less ____ means less cortisol secretion from adrenals so NEGATIVE FEEDBACK
Cytosolic inactivated glucocorticoid Hypothalamus Anterior pituitary GR Translocate Transcription factors Glucocorticoid recognition elements ACTH ACTH
In MDD you lose the negative feedback effect of cortisol so levels of cortisol increase - this can be shown by the _______ _______ test.
If after dexamethasone administration the levels of cortisol do not decrease, then there may be a 1ry defect in _______ ______ or 2r defect in ______ release.
Dexamethasone suppression test
Glucocorticoid receptor e.g. desensitised receptors
ACTH
Can use cortisol _______ inhibitors:
e.g. Ketoconazole, metyrapone
BUT although Metyrapone inhibits ______ synthesis it is not _____ and also inhibits a number of other steroid hormone processes so helps depressed patients but has intolerable side effects.
Can use selective inhibitors of ______ which inhibits the enzyme that converts __-______ to _____ (this is more _____ and doesn’t affect ______ synthesis.
Synthesis Cortisol Selective CYP11B1 11-deoxycortisol to cortisol Specific Aldosterone
Using cortisol biosynthesis inhibitors is useful in tackling the excess cortisol BUT some cortisol is needed for motivation. So would need a ______ dose of cortisol too.
Maintenance
Glucocorticoid receptors are _______ regulators.
There is the ______ receptor and the _______ receptor.
The GR: is type , NR3C (nuclear receptor 3 family _)
It has a higher affinity for _____ than _____. and is activated by ___ levels of glucocorticoid
The MR: is type , NR3C (nuclear receptor 3 family 2)
It has a higher affinity for ______ than _____. and is activated by ____ levels of glucocorticoid.
Transcriptional Glucocorticoid Mineralocorticoid 2, NR3C1 (nuclear receptor 3 family 1) Cortisol than aldosterone High
1, NR3C2 (nuclear receptor 3 family 2)
Aldosterone than cortisol
Basal
Glucocorticoid antagonists e.g. ________
_____ is an anti______ licensed in UK for termination of pregnancies BUT also affects depression related behaviours.
It blocked GR receptors so reduces ______ of ACTH and reduces ____ levels as a result.
Study by Wilson et al 2010, showed that rats given _____ in a _____ _____ ____ demonstrated less periods of ______ and more _____ (antidepressant effect). Antidepressant effect seen in patients after a follow up a few weeks after treatment.
BUT only really useful in _____ depression.
Mifepristone Mifepristone Antiprogestin transcription Cortisol Mifepristone Forced swim test Immobility Swimming Psychotic
Depressed pts have increased ___ axis activity, elevated ___ in CSF and increased ___ MRNA expression in ___ compared to nondepressed pts
Antidepressants can decrease ___ concentrations in CSF of healthy and depressed pts
HPA CRH CRH PVN (paraventricular nucleus) CRH
CRH has an agonist binding/activation region (___) a _____ region and a receptor binding/activation region (____) - both ends combine with ______ to activate it.
- NH2
- CRFBP
- COOH
- Receptor
CRH binds to two ____: _____ & ____ and initiates the ___ response to stress
GPCRs
CRFR1
CRFR2
HPA
A _____ causes an increase in ___ which mediates ____ release. This transient increase in ____ allows a stimulus assessment to determine if threats and real and allows an appropriate response to be chosen. The response is prepared an involves: Priming ____ system, _____ energy resources and activating _____ _____ system.
Stressor CRF Cortisol CRF Motor Mobilising Sympathetic nervous system
What are the two maladaptive responses to stressors?
1) Can have an exaggerated (e.g PTSD startle) or diminished response to stress (depression) (amplitude)
2) Can have a lengthened or shortened response to stress (duration)
CRF1
- most ___ activity
- peptide agonist activity ______
CRF2
- Some ___ activity
- Peptide agonist activity _____, _____ and _____
CRF
Urocortin 1
CRF
Urocortin 1, 2 & 3
CRFBP is distributed in _____ and ____.
It has ___ affinity for CRF than receptors
It _____ CRF activity by _____ and ____ up CRF so it can’t bind _____.
Plasma and CNS Higher Regulates Binding Mopping Receptors
CRFBP could be a potential target - HOW?
Could turn up CRFBP so that it prevents CRF binding to CRF receptors and causing cortisol release
CRF neurones have ___ _____ in PVN of ______.
These project to ______, _____, _____ and _____.
This means they can regulate ______ behaviour due to projections in these areas.
CRFR_ pathways modulate behavioural circuits important for _____ responding and ____ coping.
Cell bodies Hypothalamus Thalamus, dorsal raphe (5HT), locus correuleus (NA), amygdala 1 Defensive Stress
CRF has higher affinity and efficacy at CRFR_ than _.
1 than 2
CRFR’s are ____.
Stimulation by CRF or Urocortins results in _____ _____ increasing ____ production and _____ of PKA which causes ERK/MAPK production and ____ production this results in transcriptional regulation of _____ for example which is cleaved to give _____ which leads to _____ production.
GPCRs adenyl cyclase cAMP phosphorylation CREB POMC ACTH Cortisol
CRF = anxio__.
1) Overproduction of CRF in transgenic mice ______ anxiety related behaviour following exposure to novel environment (Stenzel - Poore et al 1994)
2) Injection of CRF into rats _____ anxiety related behaviours
3) ICV injection of _____ ________ to CRF in rats = anxiolytic (ICV = _____________________) (Skutella et al 1994)
4) Increased ___ plasma/CSF conc evident in anxiety and depression patients (Banki et al 1992)
Anxiogenic Increased Increased Antisense oligonucleotides blocks transcription of CRF CRF
CRFR1 knockout mice = _____ anxiety.
Stress induced release of ______ and _____ reduced.
Exploratory activity and reduced anxiety related behaviour (Timpi et al, 1998 and _____ et al, ____)
Reduced
ACTH and cortisol
Smith et al, 1998
Conditional knockout of _____ CRFR1 in mice = reduced anxiety and activity of ___ system was normal (____ et al ____). This tells us that knocking out CRFR1 in _____ (cortical region in thalamus NOT HPA) led to reduced anxiety so anxiety not just due to effects of the HPA!
Therefore, activation of CRF1R in ______ influences anxiety behaviour independent of HPA axis activity.
Forebrain
HPA
Muller at al, 2003
Forebrain
Urocortin acts at ______ and _____ anxiety hence _____ agonists may be an option in treating anxiety
CRFR2 and decreases
CRFR1
CRF mainly acts at _____ and _____ anxiety hence _____ antagonists may be an option in treating anxiety
CRFR1 and Increases
CRFR1
_____, 526 and R_____ are _____ in defensive withdrawal paradigm.
Antalarmin ____ behavioural neuroendocrine and autonomic responses to stress in non human primates.
CRA1000 reverses swim stress induced anxiety related behaviour in light dark box but ineffective in non ____ animals.
Activity of CRFR1 antagonists may depend on baseline _____.
CP154, 526 and R121919 are anxiolytic
Reduces
Stressed
Stress
R121919 (CRFR1 antagonist)
Non peptide untag of CRFR1
Good solubility and crosses ____
Improved anxiety and depression states in humans
Decreased _____ hyperactivity without entirely inhibiting ___ or ____ release.
Stopped in phase 2 trials due to _____
Z____ et al ____ and K____ et al ____
BBB HPA ACTH Cortisol Hepatotoxicity Zobel et al 2000 and Kunzel et al 2003
Metyrapone has been shown to ____ the effects of _______ in the forced swim test in rats. _____ alone caused reduction in _____ time as did metyrapone HOWEVER a combination of the drugs had a greater than ____ effect on reduction in _____ time.
- ____ et al 2005
Augment Imipramine Imipramine Immobility Additive Immobility
Rogoz et al 2005
The action of cortisol biosynthesis inhibitors has been shown to be rapid (improvement within ___) and long lasting (____) and has even proven beneficial in severely depressed pts refractory to conventional ______.
- ____ 1997
Days
Years
Antidepressants
Murphy
