Neurosteroids

Question 1

Describe the genomic actions of steroids and how these occur

Answer 1

1. Signal and hormone diffuse to the interstitial space from the bloodstream
2. Some molecules diffuse through plasma membrane of target cell
3. Steroid enters nucleus and binds to receptor complex
4. Complex attaches to target site on DNA strand
5. Activation of specific gene transcription

Question 2

Describe the time scale for genomic and non-genomic effects of steroids

Answer 2

Non-genomic effects:

• Rapid in onset - seconds/minutes
• Short in duration following disappearance of steroid from tissue

Genomic effects:

• Slower in onset - minutes/hours
• Longer in duration - persist after steroid disappears from tissue

Question 3

Name some drugs that interact with the GABAa receptor

Answer 3

Diazepam, THIP, bicuculline, alphaxalone, propofol, barbituates, etomidate

Question 4

What do early life stress events do to neurosteroid inhibition of neuronal firing?

Answer 4

ELS events increase CRF expression in the PVN and prevent the neurosteroid inhibition of neuronal firing by increasing glutamate release

Question 5

How can you increase phosphorylation of P20 (20 days pregnant) neurons?

Answer 5

Introduce a phosphatase inhibitor, stimulate PKC or add oxytocin

Question 6

How can you decrease phosphorylation of PPD1 (post-partum day 1) neurons?

Answer 6

Introduce a phosphatase stimulant, inhibit PKC or add an oxytocin antagonist

Question 7

What do drugs that target the alpha 1 subunit of the GABAa receptor cause?

Answer 7

Sedation

Question 8

What do drugs that target the alpha 2 and 3 subunits of the GABAa receptor cause?

Answer 8

Anxiolytic/analgesic effects

Question 9

What do drugs that target the alpha 5 subunit of the GABAa receptor cause?

Answer 9

Cognition

Question 10

What do drugs that target the beta 3 subunit of the GABAa receptor cause?

Answer 10

Immobility/anaesthesia

Question 11

What do drugs that target the beta 2 subunit of the GABAa receptor cause?

Answer 11

Sedation/anaesthesia

Question 12

What does NMDA receptor activation do to neurosteroid synthesis in the hippocampus?

Answer 12

NMDA receptor activation increases neurosteroid synthesis in hippocampal neurons

Question 13

If treated with finasteride what happens to the effect of NMDA receptor activation on neurosteroid synthesis in the hippocampus?

Answer 13

NMDA will no longer have an effect on neurosteroid synthesis in hippocampal neurons

Question 14

What happens to levels of progesterone during pregnancy?

Answer 14

They increase 100 fold and there is consequently an increase in allopregnanolone (5a3a)

Question 15

Which GABAa receptors decrease in some neurons during pregnancy so that 5a3a (allopregnanolone) does not cause sedation?

Answer 15

Gamma 2 and delta GABAa receptors

Question 16

What happens to neurosteroid levels postpartum?

Answer 16

Levels fall dramatically but recovery of GABAaR expression may be delayed

Question 17

What is thought to underlie postpartum depression in terms of neurosteroids and GABAa receptor expression?

Answer 17

• The mismatch in neurosteroid levels and GABAa receptor expression i.e. neurosteroid levels drop dramatically but recovery of GABAa receptor expression may be delayed postpartum
• Treat with allopregnanolone IV over 60 hours