Cerebrospinal fluid HCRT-1/OX-A is undetectable in up to 95% of patients with type 1 narcolepsy.The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus. In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle. Disturbed sleep states
The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway.
These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo. Animal models
Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience.The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder. Dog models
Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans.