Sleep

Question 1

What is the underlying neurobiology of insomnia?

Answer 1

May be explained by the disruption of CSTC loops which causes failure of filtering out sensory input by the thalamus, inducing a state of cortical arousal.
- thalamic GABAergic neurotransmission is deficient
- people with chronic pain may experience this too, as well as HPA axes malfunctioning and associated high cortisol levels

Question 2

What neurotransmitters are wake inducing?

Answer 2

Acetylcholine
- also important for focussed attention
- cholinergic neurons fire in wakefulness and REM

Serotonin and noradrenaline
- High in wakefulness, low in N123, silent in REM

Histamine
- sources from mamillary bodies
- high in wakefulness, silent in REM

Dopamine

Question 3

What neurotransmitters are sleep inducing?

Answer 3

Sleep-promoting GABA system
- originates in the ventrolateral preoptic nucleus (VLPO) and silence TMN (histamine), LC (NE), Orexin and more

Adenosine: caffeïne antagonist
- accumulates during prolonged wakefulness which may disinhibit the VLPO

Question 4

What is the stabilizer of the see-saw?

Answer 4

Orexin, it is a peptide that originates from the lateral hypothalamus.

• Orexin Cells Fire during wakefulness
• Quiet in NREM and REM

Orexin excites ACh, DA, NE, HA, and 5-
HT neuronal groups to stabilize arousal,
likely via tonic firing

Question 5

What is the underlying neurobiological mechanism of narcolepsy?

Answer 5

The lack of orexin neurons. cells are not degenerated by rather silenced by methylation.

Question 6

Describe drug to treat insomia: benzodiazepines

Answer 6

GABAa PAM facilitates GABA neurotransmission in inhibitory sleep circuits arising from the hypothalamic VLPO, which also allows for inhibition of the thalamus and better sensory filtering.

Question 7

Describe Z drugs

Answer 7

GABAa PAM that targets specifically α1 subunits, which may contribute to less dependence and is known for sedative effects -> Zolpidem

Question 8

How do drugs work that target orexin receptors?

Answer 8

Drugs for insomnia -> orexin receptor antagonists
Excessive daytime sleepiness (EDS) -> orexin receptor agonists

They are called dual orexin receptor antagonists
(DORAs) (at both orexin 1 and 2 receptors)

After administration of a DORA, arousal is no longer
enhanced and wakefulness is no longer stabilized by
orexins, and the patient goes to sleep.

At night, DORAs have more effect since there is a higher ratio of drug to orexin.

As daylight begins, orexin levels rise just as DORA levels are falling, and there is less drug relative to the amount of orexin present.

Question 9

Describe the histamine receptors

Answer 9

Histamine does not have a transporter in the cleft, so it diffuses away and can work in part via volume transmission.

The histamine receptors:
- H1 and H2 work post-synaptically
- H3 is a presynaptic inhibitory auto-receptor

Question 10

Describe the effect of light upon melatonin secretion

Answer 10

blue light supresses melatonin!

Usually, melatonin is secreted by the pineal gland under influence of light that activates the SCN