Lecture 33 - Orexin Flashcards
What are hypocretins?
- Hypothalamus specific peptides
- Neuro-excitatory activity
- OX-A and OX-B
Describe orexin receptors
- GPCRs
- OX1R & OX2R
- Regulate feeding behaviour
Describe the phenotype of mice with genetic ablation of Orexin neurons
- Narcolepsy
- Hypophagia
- Obesity
What is the effect in mice of administration of an orexin-1 receptor (OX1R) antagonist?
- Weight loss
- Anorexia
- Somnolence
Compare the effect of the following in mice:
- OX -/-
- OX1/ OX2 R -/-
- OX1 R -/-
- OX2 -/-
Narcolepsy and cataplexy phenotype in:
- OX -/-
- OX1 / OX2 R -/-
Normal:
- Only one of the receptors KO’d
Describe experimental evidence for the role of orexin in sleep regulation
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
Describe narcolepsy
- 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
What is cataplexy?
“A medical condition whereby strong emotion or laughter causes a person to suffer sudden physical collapse though remaining conscious”
REM sleep: no muscle tone
Where are orexin neurons located?
Lateral hypothalamus
Describe the synthesis of OX-A & OX-B
- HCRT gene
- HCRT mRNA
- Prepro-orexin protein
- Enzymatic cleavage into **OX-A **and OX-B
Describe sleep-wake cycles
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
Outline the effects of orexin
-
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
- Motor:
-
Appetite
- Through stimulation of NPY/AGRP neurons in ARC
Compare the inputs into the following areas of the hypothalamus
- LH
- PFA-DMH
- LH:
- Reward-related inputs
- Projections to VTA & NAc
- PFA-DMH
- Arousal-related inputs
- Projections to brainstem arousal areas
Describe the arousal system
Awake state
- Input into LH orexin neurons
- Release of orexin
- Stimulation of monoaminergic neurons
- Input into thalamus & cortex
- Awake state
Sleep state
- Input from VLPO GABA-ergic neurons
- Inhibition of orexin neurons
- Decrease in orexin
- Decrease in activity of monoaminergic neurons
- Sleep state
What was the hope for OX R antagonists?
That is would be the next generation of anti-addiction therapy
As yet, there have not been adequate studies in humans
Which compounds affect the orexin system?
What is the implication?
- 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
What is Suvorexant?
- 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
What happens to orexin when sleep pressure is high?
- High sleep pressure
- Activity of GABA-ergic VLPO neurons on OX neurons
- Inhibition of OX neurons
- Decreased OX
- Sleep
