Narcolepsy A Key Role for Hypocretins (Orexins)

tors. In contrast, prazosin, which blocks a1 noradrenerTwo recent papers have linked narcolepsy to dysfuncgic receptors, greatly exacerbates cataplexy in both tion of the newly discovered hypocretin (Hcrt) (orexin) dogs and humans. Cholinergic agonists and the cholinpeptide system. The paper by Lin et al. (1999 [previous esterase blocker physostigmine also exacerbate cataissue of Cell]) examined the genetic correlate of canine plexy, consistent with a role of cholinoceptive neurons narcolepsy, using the well-characterized Doberman in triggering muscle tone suppression. Thus, the balance pinscher and Labrador retriever models. They found a between the noradrenergic and cholinergic systems is deletion in the transcripts of the hypocretin receptor 2 a major factor in the control of cataplexy. (Hcrtr2) gene in the narcoleptic Doberman and a differIn normal individuals, postural muscles maintain some ent deletion in transcripts of the same receptor gene in level of tone throughout waking and non-REM sleep. the narcoleptic Labrador. Lin et al. speculate that these Only in REM sleep is muscle tone completely abolished. changes disrupt the proper membrane localization or This suppression of tone prevents the motor programs transduction functions of this receptor. The paper by generated in REM sleep from causing dangerous and Chemelli et al. (1999 [this issue of Cell]) used a different sleep-disrupting movements. The similarity between the approach to arrive at a similar conclusion. They created atonia in REM sleep and the atonia in cataplexy, and a knockout of the Hcrt gene in mice. Mice lacking Hcrt the abnormally short latency to REM sleep onset shown had abnormalities of sleep control resembling aspects by narcoleptics, have led to the hypothesis that cataof narcolepsy. Together these two studies implicate dysplexy may represent a triggering, in waking, of the mechfunction of the Hcrt system or systems closely linked anism that normally functions to suppress muscle tone to it in the pathophysiology of narcolepsy. The implicain REM sleep. Studies in the narcoleptic dog have suptions of these findings can best be understood by reported this hypothesis and provided insights into the viewing the nature of narcolepsy and of the Hcrt system. nature of the mechanisms controlling posture in waking. What Is Narcolepsy? Recordings of brainstem neuronal activity in narcoleptic Narcolepsy is a disease affecting approximately 1 in dogs have shown that cataplexy is linked to the activa2,000 individuals (about 125,000 in the U.S.) and usually tion of a population of cells in the medulla and pons develops in the second or third decade of life with sympthat in normal animals is active only during REM sleep toms progressing over a period of 1 or more years and (Siegel et al., 1991; Siegel, 1994). During REM sleep then stabilizing. Narcolepsy is characterized by sleepiand presumably during cataplexy, this pontomedullary ness and cataplexy, which is a loss of muscle tone trigsystem causes the release of glycine onto motoneurons, gered by sudden strong emotions such as laughter and producing hyperpolarization (Figure 1). anger. Attacks of cataplexy are usually over within secAt cataplexy onset, at the same time as glycine begins onds but in some narcoleptic patients can last for minto be released, the norepinephrine-containing neurons utes and be disabling. In contrast to sleep attacks, conof the locus coeruleus, which are normally continuously sciousness is maintained during cataplexy. In most active in waking, abruptly and completely cease disnarcoleptic patients, sleepiness rather than cataplexy charge (Wu et al., 1999). They also cease discharge in is the more troublesome symptom. Narcoleptics go REM sleep. Norepinephrine released from these neuthrough life feeling the way most of us would feel if we rons is known to facilitate motoneurons (Figure 1). Thus, had been awake for 24 hr. They awake refreshed from a combination of active inhibition and disfacilitation (renaps, but soon are sleepy again. Their nighttime sleep duced excitatory input) appears to underlie both catais fragmented with less of the deeper stages of sleep. plexy and the muscle atonia of REM sleep. Narcolepsy also has been reported in horses, cattle, What Are the Hypocretins (Orexins)? and dogs. Some cases of canine narcolepsy are spoIn 1998, de Lecea et al., using directional tag PCR subradic and these dogs cannot be bred to produce narcotraction, described a hypothalamus-specific mRNA that leptic offspring. Occasionally, entire litters are born that encoded “preprohypocretin,” which was thought to be develop the symptoms of narcolepsy at 1–4 months of the precursor of two peptides, Hcrt1 and -2. They named age and show both sleepiness and cataplexy. In the these peptides hypocretins (Hcrts) to indicate their hyearly 1970s, Dement, Mitler, and their colleagues found pothalamic localization and similarity to the gut hormone that it was possible to breed these familial narcoleptic secretin. At about the same time, Sakurai et al. (1998)