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Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness (EDS), fragmented nighttime sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis (Aldrich 1992). EDS and cataplexy, "a sudden and bilateral loss of postural muscle tone in association with intense emotion" ICSD (International classification of sleep disorders ) (Diagnostic Classification Steering Committee, Thorpy MJ, Chairman 1990), are the most disabling symptoms of narcolepsy. EDS is usually treated using amphetamine-like stimulants (Aldrich 1992;Nishino and Mignot 1997). Although stimulants reduce daytime sleepiness, they have little effect on cataplexy, and thus additional anticataplectic medications are often needed in the treatment of narcolepsy. Tricyclic antidepressants have been the most commonly used anticataplectic agents since the 1960s (Akimoto et al. 1960;Aldrich 1992;Nishino and Mignot 1997). However, tricyclics have a variety of pharmacological effects, such as anticholinergic and antihistaminergic effects and/or alpha-1 adrenergic antagonism (Baldessarini 1983). Some of these effects are responsible for a variety of side effects during chronic treatment (dry mouth, tachycardia, weight gain, sexual dysfunction, sedation, and orthostatic hypotension) (Guilleminault 1994;Thorpy and Goswami 1990). Tricyclics also significantly affect nocturnal sleep by suppressing REM sleep, increasing muscle tone and inducing nocturnal movements (Guilleminault 1994). The long-term impact of chronically disturbing sleep in narcoleptic patients due to these compounds is unknown.Canine narcolepsy is a naturally occurring animal model which presents behavioral, pharmacological and electrophysiological similarities to the human disorder Sulpiride, aD2/D3 Blocker, in Narcoleptic Dogs 529 (Baker and Dement 1985;Kaitin et al. 1986;Nishino and Mignot 1997). Narcoleptic dogs manifest a short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1999). It was recently discovered that mutations in the gene encoding a receptor for hypocretins (also called orexins) induces genetic narcolepsy in Dobermans and Labradors (Lin et al. 1999). Subsequently, it was also found that cerebrospinal fluid hypocretin-1 levels are low in human narcoleptic subjects, indicating that a deficit in hypocretin neurotransmission is also involved in human narcolepsy (Nishino et al. 2000b). Thus, the use of the canine model to uncover the pathophysiology of narcolepsy and to develop new treatments for human narcolepsy is further warranted. Previous pharmacological studies in canine narcolepsy have demonstrated that decreased monoaminergic transmission is one of the most important factors in the pathophysiology of narcolepsy (Mignot et al. 1989;Nishino et al. 1990;Nishino and Mignot 1997;Reid et al. 1998). Inactivation of catecholaminergic transmission aggravates cataplexy and/or induces sleep in these animals [see (Nishino and Mignot 1997)]. We further identified several catecholaminergic receptor subtypes specifically i...

Cholinergic stimulation in the basal forebrain (BF) triggers cataplexy in canine narcolepsy. Extracellular single unit recordings in the BF were carried out in freely moving narcoleptic dogs to study the neuronal mechanisms mediating cataplexy induction in the BF. Among the 64 recorded neurons, 12 were wake-active, three were slow wave sleep (SWS)-active, 17 were wake-/REM-active, 11 were REM sleep-active, three were cataplexy-active, and the other 18 were state-independent. Systemic administration of physostigmine, a cholinesterase inhibitor, induces status cataplecticus, decreases SWS and increases acetylcholine levels in the BF. Firing of most of the state-dependent neurons in the BF was significantly modified by physostigmine. Some of these neurons may thus mediate sleep stage changes or the effect on cataplexy observed after cholinergic stimulation in the BF.