1. Orexin / Hypocretin Hypocretins desribed in 1998 Name: Orexis = appetite infused into the Lateral Hypothalamus, it induces food intake 28 Amino-Acids peptide

2. Synapse Praeproorexin: Orexin A (hypocretin1) Orexin B ( 2) _________________________________ ________orexinA_________orexinB____ Receptors exitatory Gq ORX 1 less 2 ORX 2 and1 PLC/DAG

3. 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

4. Physiology Orexins influence Transmitters involved in the control of sleep -wakefulness cycle: Stimulation of NA, DA, TMN-histamine- neurons inhibition of ACH Orexin infused into the ventricle > wakefulness “the wakefulness transmitter“

5. 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

6. 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?)

7. Open question: Why are narcolepsy patients obese?

8. Therapy MAO-Inhibitors Modafinil

9. Modafinil (Vigil, Provigil, Vigicier, Alertec®) Approved for treatment of narcolepsy Excessive solomnescense Obstructive sleeping-apnoe Controlled by BTM

10. Modafinil Mechanisms of action α-agonist (prazosin antagonizes some effects) Facilitates Glu-transmission Reduces GABA- transmission Modafinil activates Orexin producing neurons

11. 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)

12. 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.