PHARMACOLOGICAL ASPECTS OF HUMAN AND CANINE NARCOLEPSY

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Abstract

Narcolepsy-cataplexy is a disabling neurological disorder that affects 12000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafinil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming. © 1997 Elsevier Science Ltd. All rights reserved

Abbreviations

BF
Basal forebrain
CNS
Central nervous system –
DA
Dopamine –
DAT
Dopamine transporter –
EEG
Electroencephalogram –
FECT
Food-elicited cataplexy test –
GABA
Gamma-aminobutyric acid –
GHB
Gamma-hydroxybutyrate –
HLA
Human leukocyte antigen –
5HT
5-Hydroxytryptamine (serotonin) –
LC
Locus coeruleus –
LDT
Lateral dorsal tegmentum –
MAO
Monoamine oxidase
MAOI
Monoamine oxidase inhibitor
MSLT
Multiple sleep latency test –
MWT
Maintenance of wakefulness test –
NE
Norepinephrine –
NET
Norepinephrine transporter –
PPT
Pedunculopontine tegmentum –
PRF
Pontine reticular formation –
REM sleep
Rapid eye movement sleep –
SN
Substantia nigra –
SOREMP
Sleep onset REM period –
SWS
Slow wave sleep –
TH
Tyrosine hydroxylase –
TRH
Thyrotropin-releasing hormone –
VTA
Ventral tegmental area;

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