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BMSc - Neuropharmacology and Behaviour > Neurosteroids > Flashcards

Neurosteroids Flashcards

1
Q

With use of a fish model, what is the action of progesterone metabolites in terms of effect on brain activity?

A

Rapid induction of GA

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2
Q

What is the mode of action of alphaxalone?

A

This synthetic anaesthetic steroid enhances GABAAR function

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3
Q

What is the action of 5 alpha, 3 alpha?

A

Highly potent GABAA modulator at physiological human levels

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4
Q

How are neurosteroids formed?

A

Glial cells convert cholesterol or peripherally derived progesterone to neuroactive steroids

Brains major inhibitory receptors are under the fine control of locally produced steroids

Act on synaptic receptors to prolong mIPSCS mediated by synaptic and greatly enhance extrasynaptic current (tonic inhibition)

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5
Q

Is there a physiological role of neurosteroids?

A

Examples of conditions whereby steroid levels are raised:
Acute stress
Pregnancy

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6
Q

Describe the role of neurosteroids in acute stress

A

Synaptic GABAAR of CRH-releasing PVN neurons are highly neurosteroid-sensitive

Neurosteroids prolong the mIPSP, inhibit the decay

Decreases the frequency of action potential firing frequency. In acute stress, the neurosteroids play a feedback role

Acute stress; release of glucocorticoids. The levels of neurosteroids increase which act back to decrease their excitability and release of CRH

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7
Q

Describe the role of neurosteroids in pregnancy

A

Up to the day before giving birth there are very high neurosteroid levels (100 nanomolar). This inhibition is sufficient to prevent the firing of oxytocin neurons

Parturition; 5a3a decreases, the GABAARs become neurosteroid insensitive. This results in increased neuronal firing, increased oxytocin release and therefore increase uterine contraction and lactation

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8
Q

How does the change in neurosteroid pharmacology happen in just a few hours after birth?

A

The enzyme protein kinase C is implicated in the changes to GABAAR function during pregnancy

The GABAAR beta subunit contains consensus sequences for phosphorylation by PKC/PKA on the M3 to M4 intracellular loop.
Serine 408 to serine 409

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9
Q

How is phosphorylation increased in the pregnancy period in terms of neurosteroids?

A

Increased phosphorylation can be achieved by:
Inhibiting phosphatases
Stimulation of PKC
Adding oxytocin - linked to G protein receptors, increasing PKC

This results in changes in synapses and neurosteroid insensitivity

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10
Q

How can phosphorylation be decreased in terms of neurosteroid sensitivity and what is the impact of that?

A

Stimulating phosphatases
Inhibition of PKC
Addition of oxytocin antagonist

Acts to create neurosteroid sensitive synapses

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11
Q

Describe the role of neurosteroids on behaviour in terms of specific GABAAR isoforms

A 
Alpha 1 = sedation 
Alpha 2, 3 = anxiolytic, analgesic
Beta 3 = immobility/ anaesthesia 
Beta 2 = sedation/ anaesthesia
Alpha 5 = cognition
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12
Q

Are drosophila’s GABAAR neurosteroid sensitive?

A

No

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13
Q

Where is the neurosteroid binding site on GABAARS?

A

TM1

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14
Q

Describe the characteristics of the alpha 2 knockout mice

A

Inhibitory GABAAR mediated mIPSCs of alpha 2 Q241W mice exhibit a reduced duration compared with WT

Alpha 2 Q241W mice exhibit an anxiogenic phenotype, with reduced sensitivity to anxiolytic effects of administered 5a3a

Collectively, these observations suggest that the presence of an endogenous neurosteroid tone is sufficient to influence synaptic alpha 2 GABAARs and behaviour

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15
Q

Do neurosteroids play a role in CNS develeopment?

A

Yes; early in development, synaptic GABAA receptors of thalamic VB neurons are influenced by an endogenous neurosteroid tone

Furthermore, finasteride bath on early development brain slices reduces neural inhibition

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16
Q

Does indomethacin administration have an impact on neurosteroid synthesis?

A

Yes; the synaptic inhibition enhancement effects of 5a-DHP in P20 VB neurons is prevented by indomethacin administration

17
Q

What is a trigger of neurosteroid synthesis?

A

NMDA receptor activation in the hippocampus increases neurosteroid synthesis

18
Q

Are there drugs which work to change neurosteroid levels?

A

Alcohol
If you incubate hippocampal slice in ethanol there is no effect on GABAA immediately but after around 30 mins there was a prolongation of mIPSCs which was blocked by finasteride. Furthermore, mutation of the alpha 2 GABAAR (steroid insensitive mice) reduced chronic ethanol intake

Fluoxetine
In depression, neurosteroids are abnormally low. At lower doses required for antidepressant effects, fluoxetine will increase neurosteroid production (mechanism unknown)

19
Q

Describe GABAAR expression and neurosteroid levels in pregnancy

A

Greatly raised levels of allopregnanolone

Reduced expression of GABAARs to prevent sedation, but to maintain anxiolytic/ analgesic effects

20
Q

Describe the GABAAR expression and neurosteroid levels in the post partum period

A

Dramatic decrease in allopregnanolone

GABAAR expression recovery from control is compromised in PPD

21
Q

Describe the role of brexanolone in PPD?

A

Brexanolone( 5a3a) will improve mood over 2 weeks after treatment

Brexanolone 60hrs iV infusion in patients (18-45 yrs) <6 months PP

Mood assessed at 3, 7 and 30 days following brexanolone treatment

Improved mood reported even at 30 days i.e. over 2 weeks after treatment

22
Q

Describe the effect of ORG (agonist at progesterone GPCR) on GABA transmission/ inhibition

A

ORG (agonist of progesterone GPCR) has no ACUTE effect on tonic, or phasic inhibition

In contrast to allopregnanolone in mouse hippocampal dentate gyrus granule cells, ORG has no acute (5 mins) effect upon GABA responses mediated by tonic or synaptic receptors.

Prolonged incubation with ORG however will enhance the tonic current mediated by extrasynaptic receptors with NO effect on phasic current

The ORG induced increase of the tonic current is blocked by GFX (protein kinase C inhibitor)

23
Q

How does ORG produce this delayed enhancement of the tonic current?

A

Prolonged incubation with ORG enhances surface expression of the GABAAR beta 3 subunit in cell lines

24
Q

What aspect of the beta 3 subunit does ORG and allopregnanolone target?

A

Phosphorylate the serine residues
This effect is blocked by inhibition of PKC

The GABAAR beta subunit contains consensus sequences for phosphorylation by PKC/PKA on the M3 to M4 intracellular loop (serine 408 to serine 409)

25
Q

Does the phosphorylation of the GABAAR beta 3 subunit by ORG/allopregnanolone have an influence on GABAAR trafficking?

A

In hippocampal slices both allopregnanolone and ORG increased phosphorylation of the beta 3 subunit; an effect blocked by the inhibition of PKC and PKA

The phosphorylation changes the cellular surface expression of GABAAR; phosphorylation promotes exocytosis of the GABAAR receptor

26
Q

Is the beta 3 subunit required for the effects of ORG?

A

In dentate gyrus granule cells prolonged incubation with ORG will increase the tonic current of WT mice

This effect does not occur in B3 S408/9A mice

No effect of ORG on synaptic phasic events recorded from dentate gyrus granule cells of other control or b3 S408/9A

27
Q

Describe the acute and prolonged antidepressant effects of brexanolone?

A

Acutely enhances synaptic and extrasynaptic GABAAR function

Subsequently increases the extrasynaptic cell surface expression

28
Q

Describe the therapeutic potential of neurosteroids?

A 
GA
Sedatives
Anticonvulsant
MDD 
PDD 
Analgesics
Anxiolytics
29
Q

Are the levels of neurosteroids static?

A

No; they change with the ovarian cycle, pregnancy, puberty, stress, inflammatory and neuropathic pain and development

30
Q

Describe the disease states that neurosteroids are implicated in?

A 
Epilepsy (catamenial) 
Depression 
PPD 
Anxiety 
Premenstrual Syndrome 
Neurodegenerative disorders

BMSc - Neuropharmacology and Behaviour (27 decks)

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