Narcolepsy is a neurological disorder that afflicts approximately one in 1,000 Americans. It is characterized by excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and a cluster of other symptoms related to an abnormality in rapid eye movement (REM) sleep. The disorder was originally described in 1880, but its etiology was unknown until 2000, when two groups discovered a massive loss of hypocretin (also called orexin) neurons in the hypothalamus of narcoleptic patients.

Working with researchers at the Scripps Research Institute, SRI's Dr. Thomas Kilduff co-discovered the hypocretin (Hcrt) peptides. Because narcolepsy appears to be a neurodegenerative disorder in which Hcrt-containing neurons specifically degenerate, the goal of this research project is to discover and develop a novel hypocretin receptor (HcrtR) agonist to treat narcoleptic patients without the side effects of current drugs. 

Current narcolepsy treatments are symptomatic and have a lot of room for improvement. Anticholinergics treat cataplexy, but have such undesirable side effects that patients often elect to live with this symptom. The debilitating EDS has been treated with amphetamine and other stimulant medications, which have abuse potential. More recently, gamma-hydroxybutyrate has been approved to treat both cataplexy and EDS, but the drug is a controlled substance. 

Because HcrtRs are involved in multiple physiological functions, including arousal, pain, anxiety, and reward, drugs that target the Hcrt system could be used to treat other neurological and neuropsychiatric disorders, in addition to sleepiness, insomnia, and jet lag.

The project described was supported by Award Number R21NS062168 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.