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Orexin / Hypocretin
Hypocretins desribed in 1998
Name: Orexis = appetite
infused into the Lateral Hypothalamus,
it induces food intake
28 Amino-Acids peptide
Synapse
• Praeproorexin: Orexin A (hypocretin1)
•
Orexin B (
2)
• _________________________________
• ________orexinA_________orexinB____
Receptors exitatory
Gq
ORX 1 less 2
ORX 2 and1
PLC/DAG
Distribution / neuroanatomy
• Cell bodies of orexinergic neurons are located
exclusively in the LH
• Descending projections to:
LC, SNpc/VTA, Raphe N., whole arousal system
widely into the brain stem
• Ascending projections:
The whole forebrain
Physiology
• Orexins influence Transmitters involved in
the control of sleep -wakefulness cycle:
• Stimulation of NA, DA, TMN-histamineneurons
• inhibition of ACH
• Orexin infused into the ventricle >
wakefulness
“the wakefulness transmitter“
Narcolepsy
• Dicovery some 100 years ago
• In humans and in dogs, in transgenic mutants
• Genetics predisposes
• Symptoms:
• Induced by limbic/emotional activation
• REM sleep like:
•
loss of tonus
•
dreams/hallucinations
Pathophysiology
• Orexin A is absent in the liquors of
narcolepsy patients. Orexinergic neurons
are reduced
• Orexin k. o. mutants exhibit narcolepsy
• Hypothesis: Narcolepsy is due to the
death of orexinergic neurons.
(Autoimmune disease?)
Open question:
Why are narcolepsy patients obese?
Therapy
• MAO-Inhibitors
• Modafinil
Modafinil (Vigil, Provigil, Vigicier, Alertec®)
Approved for treatment of narcolepsy
Excessive solomnescense
Obstructive sleeping-apnoe
Controlled by BTM
S
O
NH2
O
Modafinil
Mechanisms of action
α-agonist (prazosin
antagonizes some
effects)
Facilitates Glu-transmission
Reduces GABAtransmission
Modafinil activates Orexin
producing neurons
Modafinil effects in humans
Prescribed for narcolepsy, unusual fatigue,
for Parkinsonian patients
Increases vigilance (enhancement in sports)
in US-military, esp. Air Force dexedrine (go-pills) will be replaced by Modafinil
Stimulant, mood brightening
Enhances willingness to work
Meomory enhancing
Compared to amphetamines: Less jitteriness, anxiety, agitation,
no hypersolomescent rebound effect
less peripheral efects
Minimal abuse potential (Rush. et al. 2002, Behav. Pharm. 13:105-115)
Air Force testing new fatigue-combating drug
Keeps pilots awake for 88 hours and coherent, they make good decisions
and have good instrument scan patterns.