Neurobiology of Narcolepsy

Abstract

Narcolepsy is characterized by excessive daytime sleepiness and abnormal rapid eye movement sleep. It affects about 0.05% of the Caucasian population. Human narcolepsy involves the interaction of environmental factors with a specific immunogenetic background. It is tightly associated with a major histocompatibility complex allele, human leukocyte antigen (HLA) DQB1*0602. Genetic factors other than HLA are also involved. In contrast, narcolepsy in Dobermans is transmitted as a single autosomal recessive trait. This canine narcolepsy gene is unlinked to the major histocompatibility complex class II but co-segregates with a DNA segment with high homology to the human immunoglobulin μ-switch sequence, further suggesting immunopathology in narcolepsy. However, attempts to demonstrate that narcolepsy is an autoimmune disease have been unsuccessful. Narcolepsy is treated with antidepressants for rapid eye movement sleep-related symptoms and with amphetamine-like stimulants for sleepiness. Pharmacological studies using narcoleptic canines indicate that monoaminergic and cholinergic systems are involved in the pathophysiology of narcolepsy. Dopaminergic uptake mechanisms and D2(3) autoreceptors are involved in the control of alertness, whereas adrenergic uptake mechanisms, α-1 and α-2/dopaminergic D2(3) receptors, are involved in the control of cataplexy, suggesting that amphetamine-like stimulants act via the dopaminergic system and that antidepressants exhibit their anticataplectic effects via the adrenergic system. Local drug perfusion studies indicate that D2(3) agonists in the ventral tegmental area induce cataplexy and sleepiness in narcoleptic dogs but not in control dogs. Furthermore, perfusion of M2 agonists in the pontine reticular formation and the basal forebrain induces cataplexy in narcoleptic dogs. Extracellular single-unit and acetylcholine measurement studies suggest that basal forebrain cholinoceptive sites mediate the emotional trigger for cataplexy. Although narcolepsy does not seem to be a classical autoimmune disease, concomitant increases in microglial HLA class II expression with the development of the disease occur in canine narcolepsy. A neuroimmune-related process at an early age is thus likely to contribute to the neurochemical imbalance seen in narcolepsy. NEUROSCIENTIST 4:133–143, 1998