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CNS - Sarah Bailey > SB L2 - Novel Treatments > Flashcards

SB L2 - Novel Treatments Flashcards

1
Q

8 alternative theories of depression

A
  1. Stress (GC antagonists)
  2. Neuropeptides
  3. Neurogenisis
  4. Anticonvulsants (gabapentin)
  5. Inflammation
  6. Gene-enviroment interation (diet and excercise)
  7. Life long well-being
  8. Chronic illness-depression intereaction
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2
Q

Explain the HPA

A

Stress ->
Hypothalamus releases CRF

Pituitary releases ACTH

Adrenals release cortisol

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3
Q

CRF

A

Corticotrophin releasing factors

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4
Q

ACTH

A

Adrenocorticotrophic hormone

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5
Q

Effect of cortisol?

A

fight or flight response

metabolic effects, metabolizing fats for energy, glucose into the blood

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6
Q

Theory about early life stresses

A

Early life stresses known to percipitate MDD - thought that hyperactivity of HPA axis

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7
Q

Evidence of HPA involvement in depression I - depressed patients show ….

A
  1. Increased HPA axis acitvity
  2. Elevated CRF levels in the CSF
  3. increased CRF mRNA expression in the PVN

compared to non-depressed controls

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8
Q

Evidence of HPA involvement in depression I - what is the effect of antidepressant treatments on the HPA?

A

reduce CRF conc in the CS of healthy and depressed patients

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9
Q

6 Neurpeptides transmitters implicated in anxiety

A

We dont focus on these but could give e.g.:

CRF
Neurokinins (NK, substance P)
Neuropeptide Y
Cholecystokinin (CCK)
Galanin
Bombesin
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10
Q

What are neuropeptide transmitters?

A

short chain amino acid neromodulators

exerting “long-term” effects

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11
Q

Where do we find neuropeptide transmitters

A

brain regions mediating emotional behavior/respond to stress

e.g. hypothalamus, amgdala

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12
Q

Neropeptide transmitters modulate ………………….. known to be involved in anx/depression

A

Neropeptide transmitters modulate neurotrasmitter systems known to be involved in anx/depression (e.g. 5HT, NA)

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13
Q

CRF has 3 relat4ed peptides:

A

urocortin 1,2,3

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14
Q

Describe the receptors for CRF

A

GPCRs - two types

CRFR1 and CRFR2

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15
Q

What happens when CRF binds to it’s receptor

A

intiates HPA resonpse to stress

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16
Q

What happens when CRF binds to it’s receptor

A

initiates HPA response to stress

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17
Q

describe the regions of the CRF molecule

A

agonist blinding/activation on each side

CRFBP binding in the middle (where the binding protein binds)

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18
Q

What is CRFBP and its function?

A

CRF binding protein - we don’t know what it’s for but perhaps to regulate CRF availability?

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19
Q

Where is CRFBP found?

A

ditributed in the plasma

20
Q

What has higher affinity, CRFBP or CRFR?

A

binding protein!

21
Q

What has higher affinity, CRFBP or CRFR?

A

binding protein!

22
Q

Where are the CRF pathways in the brain?

A

Extend to the central nucleus of amygdala, PVN of the hypothamaus, and raphe nuclei

23
Q

Where is CRFR1 and CRFR2 found

A

CRFR1 - WIDESPREAD DISTRIBUTION (frontocortical areas, amygdala, locus coeruleus, cerebellum, pituitary)

CRFR2 - DISCRETE LOCALISATION - (hypothalamus, amygdala, raphe)

24
Q

What happens in the cell when the CRFR is stimulated (2)

A
  1. Transcriptional regulation (e.g. POMC)
  2. Stumulation of NO synthase, prostaglandins
  • Different ligands may differentially activate signalling cascades in a cell-type specific manner
25
3 animal evidences that CRF is axiogenic | 2 refs - these refs are not in the extra reading so maybe only learn the facts
Overproduction of CRF in transgenic mice increases anxiety-related behaviour (Stenzel-Poore et al. 1994) Injections of CRF into rats increases anxiety-related behaviours ICV injection of antisense oligonucleotides to CRF in rats is anxiolytic (Skutella et al. 1994)
26
Evidence that CRFR1 (across whole brain) receptor knockout mouse has reduced anxiety 1 ref
1. stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced 2. increased exploratory activity and reduced anxiety-related behaviour (Timpl et al. 1998, Smith et al. 1998)
27
1 human evidence that CRF is axiogenic | 1 ref - these refs are not in the extra reading so maybe only learn the facts
Increased CRF plasma/CSF concentrations evident in anxiety and depression patients (Banki et al. 1992)
28
what is ICV injection
intracerebroventricular
29
Evidence that CRFR1 (forebrain only) receptor knockout mouse has reduced anxiety 1 ref
Conditional knockout of forebrain CRFR1 in mice showed reduced anxiety, and the activity of the HPA system was normal (Muller et al. 2003)
30
Evidence that CRFR1 (forebrain only) receptor knockout mouse has reduced anxiety 1 ref
Conditional knockout of forebrain CRFR1 in mice showed reduced anxiety, and the activity of the HPA system was normal (Muller et al. 2003)
31
Explain the counter-regulatory mechanism for CRFR1/2? 2 therapeutic targets this presents?
*See diagram* CRF stimulates CRFR1 increasing anxiety Urocortin stimulates CRFR2 decreasing anxiety Targets: CRFR1 antagonism & CRFR2 agonism
32
do CRFR2 agonist work?
No - they actually increase anxiety showing that our theory is a bit wrong?
33
Activity of CRFR1 antagonists may be dependant on... | how is this shown and name of molecule
base line stress becuse CRA1000 reverses swim-stress induced behaviour in the light dark box but is ineffective in non-stressed animal
34
3 molecules that show CRFR1 is anxiolytic
1 CP154,526 and R121919 are anxiolytic in a defensive withdrawal paradigm 2 Antalarmin reduces the behavioural, neuroendocrine and autonomic responses to stress in non-human primates 3 DMP904 increases time spent in open arms of EPM
35
Talk about R121919: - type of molecule? - crosses the BBB? - action on humans? how?
Non-peptide antagonist of CRFR1. Good solubility/corsses BBB Improved anxiety and depression states in humans - reduces HPA hyperactivity without entirely inhibiting ACTH or cortisol release
36
why is R121919 not used
hepatotoxic
37
why is it good to not entiresly supress the HPA?
You still need some basal cortisol levels
38
why is it good to not entiresly supress the HPA?
You still need some basal cortisol levels
39
What canc MDD patients tell us? 3
1. Conc of cortisol in urine is increased - evidence of HPA involvement in depression 2 feedback of HPA is inhibited (shown by dexamethasone supression test) 3 sucessful antidepressant treatments restores HPA function
40
Dexamethasone supression test is a key indicator of
whether a patients will relapse
41
How does dex supression test work?
Dex given at night - it feedsback preventing normal morning cortisol levels being produced. Test cortisol levels at 8am. In a normal person they are low. If depressed this doesn't happen as they don't get -ve feedback - the HPA isn't working.
42
2 e.g. of cortisol synthesis inhibitors
e.g. ketoconazole, metyrapone
43
do cortisol synthesis inhibitors work? Problem?
yes - provided you give a maintenance dose of cortisol in addition. It targets the synthesis of all the hormones in the pathway - really we would like to inhibit the final step (selective inhibition of CYP11b1)
44
2 types of receptors cortisol binds to
Type 1 (Mineralocorticoid) - activated by aldosterone - activated by basal glucocorticoid receptor ``` Type 2 (Glucocorticoid) -activated by elevated levels of glucocorticoid ```
45
Name a glcocorticoid antagonist is it good?
mifepristone (RU-486) (abortion treatment) not extensively used but shows less time spent immobile in forced swim test short period evidence says it help depression and particularly psychiatric symptoms

CNS - Sarah Bailey (9 decks)

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