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BIOM30001 - Frontiers in Biomedicine > Lecture 33 - Orexin > Flashcards

Lecture 33 - Orexin Flashcards

1
Q

What are hypocretins?

A
  • Hypothalamus specific peptides
  • Neuro-excitatory activity
  • OX-A and OX-B
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2
Q

Describe orexin receptors

A
  • GPCRs
  • OX1R & OX2R
  • Regulate feeding behaviour
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3
Q

Describe the phenotype of mice with genetic ablation of Orexin neurons

A
  • Narcolepsy
  • Hypophagia
  • Obesity
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4
Q

What is the effect in mice of administration of an orexin-1 receptor (OX1R) antagonist?

A
  • Weight loss
  • Anorexia
  • Somnolence
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5
Q

Compare the effect of the following in mice:

  • OX -/-
  • OX1/ OX2 R -/-
  • OX1 R -/-
  • OX2 -/-
A

Narcolepsy and cataplexy phenotype in:

  • OX -/-
  • OX1 / OX2 R -/-

Normal:

  • Only one of the receptors KO’d
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6
Q

Describe experimental evidence for the role of orexin in sleep regulation

A

Rat experiments

  • Orexin KO → narcolepsy in mice
  • OX1&2R KO → narcolepsy
    • ​Both receptors must be KO’d to see narcolepsy/cataplexy

Humans

  • Nacrolepsy:
    • ​Absence of orexin peptides:
    • Orexin functions like a switch
    • If the switch doesn’t work, the individual
      oscillates between the two states
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7
Q

Describe narcolepsy

A
  • Intermittend periods of sleep during the day and wake during the night
  • Sleep quality is poor across the board
  • Basis
    • ​Defect in orexin
    • Orexin is the switch that turns sleeping on or off
    • Without the switch, there is continual oscillation between the two states
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8
Q

What is cataplexy?

A

“A medical condition whereby strong emotion or laughter causes a person to suffer sudden physical collapse though remaining conscious”

REM sleep: no muscle tone

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9
Q

Where are orexin neurons located?

A

Lateral hypothalamus

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10
Q

Describe the synthesis of OX-A & OX-B

A
  1. HCRT gene
  2. HCRT mRNA
  3. Prepro-orexin protein
  4. Enzymatic cleavage into **OX-A **and OX-B
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11
Q

Describe sleep-wake cycles

A

Mechanism:

  • Sleep pressure
    • ​Increases as a function of time awake
    • ​Subsides gradually during sleep
    • Wake once sufficiently low
  • Circadian rhythm
    • ​Sine curve
    • Increases just before waking
    • Decreases towards end of wakefulness
  • Orexin
    • ON/OFF switch
    • ​Wake:
      • ​Orexin neurons are active
      • Orexin levels high
      • Phasic bursts as a function of **motivational state **and certain behaviours
    • Sleep:
      • ​Orexin neurons are silent
      • Orexin neuron discharge helps combat sleep pressure & initiation
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12
Q

Outline the effects of orexin

A
  • Digestion
    • ​Stimulates vagus nerve
    • → cephalic phase of digestion
  • Reward
    • ​Through stimulation dopaminergic centres
  • Arousal
    • Motor:
      • Through stimulation of dopaminergic centres
    • Emotional:
      • ​Through stimulation of limbic centres
  • Appetite
    • ​Through stimulation of NPY/AGRP neurons in ARC
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13
Q

Compare the inputs into the following areas of the hypothalamus

  • LH
  • PFA-DMH
A
  • LH:
    • Reward-related inputs
    • Projections to VTA & NAc
  • PFA-DMH
    • Arousal-related inputs
    • Projections to brainstem arousal areas
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14
Q

Describe the arousal system

A

Awake state

  1. Input into LH orexin neurons
  2. Release of orexin
  3. Stimulation of monoaminergic neurons
  4. Input into thalamus & cortex
  5. Awake state

Sleep state

  1. Input from VLPO GABA-ergic neurons
  2. Inhibition of orexin neurons
  3. Decrease in orexin
  4. Decrease in activity of monoaminergic neurons
  5. Sleep state
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15
Q

What was the hope for OX R antagonists?

A

That is would be the next generation of anti-addiction therapy

As yet, there have not been adequate studies in humans

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16
Q

Which compounds affect the orexin system?

What is the implication?

A
  • Compounds:
    • Morphine
    • Food
    • Cocaine
    • Alcohol
  • Effect:
    • Increase activity of the orexin neurons in the lateral hypothalamus (LH)
  • Implication:
    • ​Orexin is involved in drug dependence
    • Antagonist could be used for drug dependence therapy
17
Q

What is Suvorexant?

A
  • OX R antagonist
  • Schedule IV: compound found to be borderline addictive
  • High doses scrapped by FDA
  • Low doses now approved
  • Use:
    • New insomnia drug
    • Aiming to decrease morning grogginess (biggest problem with Z drugs)
  • Strict prescribing conditions
    • 30mins before sleep, 7 hrs before waking etc.
    • Contraindicated in narcolepsy
18
Q

What happens to orexin when sleep pressure is high?

A
  1. ​High sleep pressure
  2. Activity of GABA-ergic VLPO neurons on OX neurons
  3. Inhibition of OX neurons
  4. Decreased OX
  5. Sleep

BIOM30001 - Frontiers in Biomedicine (35 decks)

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