Vol. 21, No.
7 July 1999
CE Refereed Peer Review
FOCAL POINT
★The clinical signs of narcolepsy
are related to alterations in the
neurotransmitter systems that
regulate the sleep–wake cycle.
KEY FACTS
■ Cataplexy is the most frequent
clinical sign of narcolepsy in
domesticated animals.
■ Narcolepsy is inherited as an
autosomal recessive trait in
Doberman pinschers and
Labrador retrievers but is
genetically complex in other
canine breeds.
■ Cholinergic hypersensitivity
and adrenergic hypoactivity
are thought to play a dominant
role in cataplexy; dopaminergic
hypoactivity may be associated
with the expression of daytime
sleepiness.
■ Tricyclic antidepressants, in
general, are successful in
treating cataplexy, whereas the
amphetamine-like stimulants
are more effective in treating
excessive daytime sleepiness.
20TH ANNIVERSARY
Canine Narcolepsy
and the Role of the
Nervous System
Tuskegee University
Elaine S. Coleman, DVM, PhD
ABSTRACT: Narcolepsy is a neurologic disorder of excessive sleep reported in both humans
and domesticated animals. Cataplexy, which is a brief episode of weakness induced by excite-
ment or strong emotion, is the most frequently noted clinical sign of narcolepsy in domesti-
cated animals. Underlying alterations in the neurotransmitter systems regulating the
sleep–wake cycle have been implicated in the pathophysiology of narcolepsy. This article dis-
cusses the clinical syndrome of narcolepsy, including clinical signs, diagnosis, and treatment,
and the underlying altered neurotransmission responsible for narcoleptic attacks.
H
umans and domesticated animals can both be affected by narcolepsy, a
neurologic disorder of excessive sleep. In humans, the classic character-
istics of narcolepsy are a tetrad of clinical signs consisting of excessive
daytime sleepiness, associative disturbances of cataplexy, sleep paralysis, and hyp-
nagogic hallucinations.1–3 Nocturnal sleep disturbances are also commonly seen.
In domesticated animals, the most frequent clinical sign of narcolepsy is cata-
plexy, although excessive daytime sleepiness and fragmented sleep patterns have
been reported.4–7 Narcolepsy has been documented in more than 15 breeds of
dogs, one cat, cattle, horses, and ponies.8–14 This article focuses on the clinical
syndrome of narcolepsy in domesticated animals and discusses our current un-
derstanding of the underlying pathophysiology.
CLINICAL SIGNS
Narcoleptic episodes in domesticated animals are usually elicited by emotion-
al stimulation, including excitement, eating or drinking, playing, sexual activity,
being let out of a cage or stall, and greeting owners.8,12 Cataplexy is a brief epi-
sode of weakness without altered consciousness that is induced by excitement or
strong emotion.1–3 Pelvic limbs and neck muscle groups are frequently affected
during a cataplectic attack.1
The severity of cataplexy can vary from mild stumbling (i.e., partial attack) to
an acute collapse of atonic and areflexic paralysis lasting from a few seconds to
several minutes (i.e., complete attack).15 The eyes are usually open and blinking,
and the animal visually tracks objects.16 Prolonged narcoleptic episodes can be
associated with signs typical of rapid eye movement (REM) sleep, including
twitching of the distal musculature, facial grimaces, REM, and weak vocaliza-
Small Animal/Exotics 20TH ANNIVERSARY
tions.1,15–17 The episodes may be interrupted by external
stimulation, such as petting or shaking the animal or
making loud noises.15,16 Attacks vary in frequency, oc-
curring many times a day or several times a month. Ex-
cess sleepiness and fragmented sleep patterns have also
been reported in dogs with narcolepsy. 1,6,7,16 Narcolep-
tic dogs have a much shorter sleep latency (i.e., period
of onset to sleep) than do normal dogs.6 In general, the
disorder develops acutely and signs stabilize within a
week with little change in severity.17
In humans, narcolepsy usually begins in the second
or third decade of life.3 In dogs, narcolepsy tends to oc-
cur at a young age (younger than 6 months) but has
been reported in dogs as old as 7 years of age.15,16 There
is no apparent sex predisposition in humans or domes-
ticated animals.3 However, a recent report demonstrat-
ed that cataplexy was more severe in female than in
male narcoleptic Dobermans in five of six affected lit-
ters.18
NEUROPHYSIOLOGY OF SLEEP
There are two basic forms of sleep—slow-wave sleep
(SWS) and REM sleep.16,19 SWS can be further subclas-
sified as light or deep.16 SWS is the initial period of
sleep and is characterized by decreases in body and
brain temperature, brain glucose utilization, cerebral
blood flow, heart and respiratory rates, and blood pres-
sure.20–23 Electroencephalographic (EEG) characteristics
progress from fast, low-amplitude, asynchronous waves
in the awake state to slow, large-amplitude, syn-
chronous brain waves in SWS.16 REM sleep, which is
considered the period of visual dreaming, is character-
ized by increased body and brain temperature com-
pared with SWS as well as increases in brain glucose
utilization, cerebral blood flow, heart rate, and blood
pressure.21–23 Respiration becomes irregular, shallow,
and more rapid in REM sleep. Although muscle twitch-
ing may be evident during REM sleep, most of the pos-
tural muscles are atonic.16,23 EEG patterns return to the
high-frequency, low-amplitude wave characteristic of
the awake state.16,21
The duration of REM sleep varies with the length of
the sleep cycle, which increases with body and brain
size among species.22 In humans, each sleep cycle (from
the beginning of SWS through REM sleep) lasts ap-
proximately 90 to 110 minutes. The REM period lasts
for 5 to 10 minutes during the first sleep cycle, whereas
it may last for 40 to 60 minutes in later sleep cycles.21
In dogs and cats, SWS lasts 10 to 15 minutes and REM
sleep lasts approximately 5 minutes.19,22,24
Neuroanatomic areas involved in the generation of
the sleep–wake cycle have been identified through vari-
ous transection, ablation, and chemical stimulation ex-
SLOW-WAVE SLEEP ■ SLEEP–WAKE CYCLE ■ CHOLINERGIC NEURONS
Compendium July 1999
periments at different levels of the neuraxis. Selective
cell groups and neurotransmitter systems within the
brain stem and forebrain are known to play a major role
in the regulation of the cycle. The occurrence of the
sleep–wake cycle involves an interaction between
monoaminergic neurons (which produce monoamine
neurotransmitters, such as norepinephrine and sero-
tonin) and cholinergic neurons (which produce acetyl-
choline) of the upper brain stem. Specifically, noradren-
ergic neurons in the locus coeruleus (LC), serotonergic
neurons in the dorsal raphe nucleus (DRN), and cholin-
ergic neurons in the pontomesencephalic tegmentum
(pedunculopontine tegmental nucleus and laterodorsal
tegmental nucleus) play a major role in the sleep–wake
cycle.1,22,23
Neurons from the LC project diffusely into the entire
central nervous system, including the cerebral cortex,
hypothalamus, hippocampus, and brain stem. 1,25,26
During the awake state, noradrenergic neurons in the
LC and serotonergic neurons in the DRN are tonically
active and account for the alert mental status and cor-
tical activation demonstrated on EEG recordings.1,22,23,27–29
In addition, cholinergic neurons located in the pon-
tomesencephalic region of the brain stem and basal
forebrain are believed to play a role in activating the
cerebral cortex during the awake state as well as during
REM sleep, with tonic discharges recorded from these
neurons during both periods (Figure 1).1,27,28 Dopamin-
ergic neurons located in the midbrain may also play a
role in cortical activation in the awake state but are not
believed to play as major a role as norepinephrine and
serotonin in the regulation of the sleep–wake cycle.1
Progression from the awake state to SWS is charac-
terized by decreased firing of neurons in the LC and
DRN.22 Cholinergic neurons in the pontomesencephal-
ic region discharge at a lower rate than during the
awake and REM states.23,27,28
With the onset of REM sleep, neurons in the LC and
DRN cease firing altogether, whereas cholinergic neu-
rons in the pontomesencephalic region discharge at a
maximal rate (Figure 1). 22,23,27,28 The importance of
these cholinergic neurons is evident by the fact that
REM sleep and REM sleep atonia are produced by
chemically stimulating the cholinergic system within
the pontine brain stem.23,30 These cholinergic neurons
have ascending projections to the thalamus, hypothala-
mus, and basal forebrain and play a major role in corti-
cal activation (via thalamocortical pathways) during
REM sleep.25,31,32 Cortical projections from cholinergic
neurons of the basal forebrain (nucleus basalis, substan-
tia innominata, diagonal band, septum) are also
thought to play a role in the cortical activation seen in
REM sleep.1,27,28 Cholinergic neurons in the pontomes-
Compendium July 1999 20TH ANNIVERSARY Small Animal/Exotics

encephalic region send descending projections to the
medullary reticular formation to inhibit spinal cord ac-
tivity, leading to the muscle atonia characteristic of
REM sleep.22 Sensory transmission and autonomic re-
flexes are also suppressed during this period.22 REM
sleep is therefore a paradoxic state of sleep in which
cerebral cortical activity is similar to that of the awake
state, yet muscle tone, sensory input, and autonomic
reflexes are dramatically decreased.22
The monoaminergic neurons in the LC and DRN
and the cholinergic neurons in the pontomesencephalic
tegmentum interact with one another in regulating the
different stages of the sleep–wake cycle (Figure 1).22,33
Cholinergic neurons in the pontomesencephalic teg-
mentum are under inhibitory restraint by the mono-
aminergic neurotransmitters (particularly serotonin
from the DRN29) during the awake state and fire only
in response to strong stimuli.23 Cholinergic activity in
the pontomesencephalic tegmentum increases during
REM sleep at a time when LC and DRN activity ceas-
es.1,22,23,27–29 A summary of the activity of the mono-
aminergic and cholinergic neurotransmitter systems
during the sleep–wake cycle can be found in Table I.
Other mediators potentially involved in the regulation
of the sleep–wake cycle include γ-aminobutyric acid,
opiates, adenosine, histamine, dopamine, glutamate,
and thyrotropin-releasing hormone.1,29 The specific role
of these mediators in the sleep–wake cycle is currently
under investigation.
PATHOPHYSIOLOGY OF NARCOLEPSY
Genetics
Narcolepsy is thought to have a hereditary basis in
both humans and domesticated animals. The incidence
of narcolepsy in humans is 0.03% to 0.16%3,34; a high-
er incidence (0.8% to 4%) occurs among humans who
are related.35–37 Narcolepsy has been reported in many
canine breeds, including the Doberman pinscher, Lab-
rador retriever, miniature poodle, beagle, dachshund,
Saint Bernard, malamute, springer spaniel, standard
poodle, Airedale, Afghan, Welsh corgi, Irish setter,
wirehaired griffon, giant schnauzer, and rottweiler as
well as several mixed breeds.16,38
In most affected breeds of dogs (including poodles,
beagles, and dachshunds), narcolepsy is believed to be
genetically complex because it has not been possible to
establish affected breeding colonies.1,39,40 Narcolepsy in
Doberman pinschers and Labrador retrievers is trans-

Figure 1A Figure 1B
Figure 1––Interactions between monoaminergic (MA) and cholinergic (ACH) neurons of the brain stem during the sleep–wake
cycle.22,27,28 (A) During the awake state, MA neurons from the locus coeruleus (LC; norepinephrine) and dorsal raphe nucleus
(DRN; serotonin) are active and account for the aroused state of the cerebral cortex. Neurons from the LC project diffusely
throughout the central nervous system, including the cerebral cortex, thalamus (TH), hypothalamus, brain stem, and hippocam-
pus. ACH neurons in the pontomesencephalic tegmentum are tonically discharging during the awake state but at a lower level
than that seen during rapid eye movement (REM) sleep, partly because of inhibitor input from serotonergic neurons of the
DRN. These ACH neurons project to the TH, hypothalamus, basal forebrain (BF), and brain stem. ACH neurons found in the
BF project into the cerebral cortex and, along with those of the pontomesencephalic tegmentum (via thalamic relays), assist in
cortical activation during the awake state. (B) During REM sleep, MA neurons of the LC and DRN cease firing altogether,
whereas ACH neurons of the pontomesencephalic tegmentum increase their rate of firing. Cholinergic input relayed to the cere-
bral cortex from the pontomesencephalic tegmentum and the BF during REM sleep accounts for the increased activity seen on
the electroencephalogram, creating patterns similar to those in the awake state. Projections of ACH neurons to the medullary
reticular formation (MRF) result in inhibition of spinal cord activity, leading to the muscle atonia characteristic of REM sleep.
(P = pituitary.)

MONOAMINERGIC NEUROTRANSMITTERS ■ INCIDENCE ■ AFFECTED BREEDS

Small Animal/Exotics 20TH ANNIVERSARY Compendium July 1999

TABLE I set of cataplexy in relation to stimuli

Neuronal Activity During the Sleep–Wake Cycle1,22,23,27–29 that cause excitement.1
In addition to hypersensitivity to
Awake Slow-Wave Sleep Rapid Eye Movement cholinergic stimulation, pharmaco-
Norepinephrine (LC) Active Decreased Cease firing logic studies suggest that mono-
aminergic hypoactivity may play a
Serotonin (DRN) Active Decreased Cease firing role in canine narcolepsy.1 Drugs
that interfere with the actions of
Acetylcholine Active Decreased Maximal activity monoamines exacerbate cataplexy,1
(PPN/LDT)a (less than REM) whereas all therapeutic agents cur-
a rently used to treat narcolepsy en-
A small group of neurons in this region increase their firing rate as sleep moves from the
awake stage (low activity) to slow-wave sleep to rapid eye movement (maximal activity). 27,28 hance monoaminergic activity. 44
DRN = dorsal raphe nucleus; LC = locus coeruleus; PPN/LDT = pedunculopontine nu- Tricyclic antidepressants used to
cleus/laterodorsal tegmental nucleus found in the pontomesencephalic tegmentum; REM treat cataplexy have a number of
= rapid eye movement. pharmacologic actions, including
monoamine reuptake inhibition
(norepinephrine, epinephrine,
mitted as a simple autosomal recessive trait with full dopamine, and serotonin), anticholinergic activity, and
penetrance.1,39,40 Breeding colonies for Dobermans and α1-adrenergic antagonistic and antihistaminergic ef-
Labradors established at the Stanford Sleep Disorder fects.1 By using selective monoamine reuptake blockers
Center in Palo Alto, California, have been instrumental that lack other pharmacologic effects, it was deter-
in elucidating the pathophysiology of narcolepsy in mined that the adrenergic reuptake inhibition was the
both humans and domesticated animals. Narcolepsy key activity accounting for the anticataplectic effect of
may also result from such acquired causes as trauma, the tricyclic antidepressants.1 Serotonergic and dopa-
3,16,17
infection, or inflammation. minergic reuptake inhibitors had little or no effect on
cataplexy.1
Neurochemical Alterations Further studies of the tricyclic antidepressants dem-
Many researchers believe that narcolepsy is associated onstrated that the desmethyl metabolites were more ef-
with widespread hypersensitivity to cholinergic stimula- fective against cataplexy than was their parent com-
tion, particularly involving the pontine reticular forma- pound.1 In addition, α1 adrenergic agonists decreased
1
tion. Cholinergic mechanisms are important in con- cataplexy, whereas adrenergic antagonists exacerbated
trolling REM sleep and REM sleep atonia as indicated canine cataplexy.1 However, the side effects associated
by increased cholinergic neuron activity during this pe- with the α1 adrenergic agonists, such as vasoconstric-
riod.1,23 Stimulation of the pontine reticular formation tion, high blood pressure, and reflex bradycardia, limit-
by local injection of cholinergic agonists triggers REM ed their clinical use.1 α2-Antagonists, which increase the
41
sleep and cataplectic-like attacks in dogs. Similarly, in- release of norepinephrine, have been shown to decrease
creased acetylcholine release in the pontine reticular cataplexy in dogs.45 Although yohimbine, an α2-antago-
42
formation occurs during spontaneous cataplexy in dogs. nist, can effectively decrease cataplexy in dogs, the ben-
Cholinergic neurons are also located in the basal eficial effect is short during chronic administration.1 β-
forebrain region (nucleus basalis, substantia innomina- adrenergic agonists and antagonists did not consistently
ta, diagonal band, and septum).1 In narcoleptic dogs, alter cataplexy, except at high dosages.
direct stimulation of the basal forebrain with carbachol A combination of cholinergic hypersensitivity and
(a cholinergic agonist) is associated with cataplexy.43 In monoaminergic hypoactivity in the pathophysiology of
normal dogs and cats, stimulation of the basal forebrain narcolepsy is further supported by pharmacologic stud-
area with carbachol is associated with increased alert- ies in heterozygous Dobermans; these dogs, which carry
ness. However, stimulating the basal forebrain of nor- the gene for narcolepsy, do not exhibit spontaneous cat-
mal dogs with higher dosages of carbachol leads to cata- aplexy.46 However, combined administration of a cholin-
plexy, suggesting that narcoleptic dogs are more ergic agonist and a drug that inhibits monoaminergic
sensitive than are normal dogs to cholinergic activity transmission induced cataplexy in two thirds of asymp-
and the induction of cataplexy.43 The basal forebrain is tomatic, heterozygous, narcoleptic Dobermans, whereas
tightly connected to the limbic system, which, com- control dogs remained asymptomatic.46 Administration
bined with this region’s hypersensitivity to cholinergic of either compound alone failed to induce cataplexy in
stimulation in narcoleptic animals, may explain the on- the heterozygous Dobermans.

BREEDING COLONIES ■ BASAL FOREBRAIN STIMULATION ■ TRICYCLIC ANTIDEPRESSANTS

Compendium July 1999 20TH ANNIVERSARY Small Animal/Exotics

Although adrenergic and adrenergic receptors have

cholinergic systems are im-
portant for the regulation of
cataplexy, recent studies show
that dopamine is important
in the regulation of sleepi-
ness and expression of exces-
sive daytime sleep seen in
narcoleptic patients.1 Mid-
brain dopaminergic systems
project widely to the cere-
bral cortex in monkeys and
humans and are believed to
play a role in cortical activa- Figure 2—Cholinergic hypersensitivity and adrenergic (partic- lieve that cholinergic hyper-
tion.1 Stimulants used to treat ularly noradrenergic) hypoactivity are thought to play a dom- sensitivity and adrenergic
excessive daytime somno- inant role in cataplexy; dopaminergic hypoactivity may be hypoactivity play a more
lence of narcolepsy are asso- more involved in the expression of excessive daytime sleepi- dominant role in cataplexy,
ciated with increased EEG ness.1
arousal; their effects are at-
tributed to stimulation of
monoaminergic transmission via stimulation of nore-
pinephrine, dopamine, or both.1
A more thorough assessment of the mechanistic ac-
tions of stimulants suggests that modulation of
dopamine activity plays a greater role in mediating
EEG arousal than does norepinephrine.1 Administra-
tion of dopamine reuptake inhibitors increased EEG
arousal dose dependently in narcoleptic dogs; however,
two norepinephrine reuptake inhibitors (desipramine
and nisoxetine), which completely suppressed cata-
plexy, had no effect on EEG arousal.47 Amphetamines,
which increase dopamine release and decrease
dopamine reuptake, had the greatest effect on EEG
arousal.
Recent studies suggest that dopaminergic systems
may have a role in cataplexy. In the ventral tegmental
area of the midbrain, autoreceptor stimulation of D2 re-
ceptors (which decreases the release of dopamine) in-
creases cataplexy and sleepiness in narcoleptic dogs,
suggesting that dopaminergic hypoactivity in the ven-
tral tegmental area may be involved in cataplexy.1 This
is in contrast to previous studies in which dopamine
was believed to play no role in cataplexy based on a
lack of effect of dopaminergic agonists (reuptake block-
1
ers). The fact that cataplexy does not respond to
dopamine reuptake inhibitors while being exacerbated
via stimulation of dopaminergic autoreceptors may re-
late to anatomically distinct dopaminergic systems in
specific brain regions.1 Further studies are needed to
clarify the role of dopamine in cataplexy.
Alterations in receptor numbers and neurotransmit-
ter release may account for the underlying disturbances
leading to narcolepsy. Alterations in cholinergic and
been reported in narcoleptic
dogs, including increases in
muscarinic acetylcholine M2
receptors in the pons,48,49 α1
receptors in the amygdala,50
and α2 receptors in the LC.51
Similarly, increased D2 re-
ceptors in the amygdala and
nucleus accumbens have
been reported in narcoleptic
dogs.52
Researchers currently be-
whereas dopaminergic hy-
poactivity is more involved
in the expression of daytime
sleepiness (Figure 2).1,53 An in-depth review of the neu-
rochemical alterations involved in narcolepsy is avail-
able in the literature.1
Immune System Involvement
In humans, narcolepsy is closely associated with the
specific human leukocyte antigen markers DQB1*0602
and DR2.1,3,54 Canine narcolepsy is associated with a
gene called canarc-1, which has been linked to a DNA
segment with high homology to a human µ-switch im-
munoglobulin gene.55,56 In addition, an increase in ma-
jor histocompatibility complex class II expression in the
central nervous system has been reported in narcoleptic
dogs.57,58 Despite these findings, an autoimmune mech-
anism has been difficult to establish.54 Whether the im-
mune system is directly or indirectly involved in the
underlying pathophysiology of narcolepsy remains to
be determined.
DIAGNOSIS
Diagnosis of narcolepsy in veterinary medicine is
usually based on history and characteristic signs of cata-
plexy (e.g., acute onset of collapse associated with ex-
citement, flaccid paralysis, and rapid recovery).15,16 The
fact that cataplexy is typically associated with excite-
ment, such as that elicited by eating, is the basis for the
food-elicited cataplexy test (FECT).
The FECT is conducted by placing ten pieces of
food (0.5 cm3) in a row, 14 inches (30.5 cm; for small
breeds) or 23 inches (50 cm; for large breeds) apart.8,16
A normal animal can consume the food in a short time
(less than 45 seconds).8 Narcoleptic animals may need
more time (more than 2 minutes) to consume the food

DOPAMINE ■ CANARC-1 ■ FOOD-ELICITED CATAPLEXY TEST

Small Animal/Exotics 20TH ANNIVERSARY
because of triggered episodes of partial or complete cat-
aplexy, evident on observation of the test. Small breeds,
in which narcolepsy is often more severe, frequently
have very prolonged times (5 to 15 minutes) to com-
plete the FECT compared with narcoleptic dogs of
larger breeds.16 It is preferable to perform the test in the
home environment to avoid the stress of a veterinary
hospital setting, which could prevent the manifestation
of attacks.8
Mildly affected animals may require pharmacologic
testing to confirm a cataplectic attack. Physostigmine
salicylate, a cholinesterase inhibitor that crosses the
blood–brain barrier, is administered intravenously (0.025
to 0.1 mg/kg) and increases the chances of spontaneous
or elicited cataplectic attacks within 5 to 15 minutes in
susceptible animals.16,59 Potential side effects of physo-
stigmine include salivation and diarrhea; a low dose
should therefore be used initially. 16 Neostigmine, a
cholinesterase inhibitor that does not cross the blood–
brain barrier, is not effective in eliciting cataplexy.
Pharmacologic manipulation to reduce the incidence
of elicited cataplectic episodes also may be used diag-
nostically. After a FECT or observation for cataplectic
attacks during play periods, atropine sulfate (0.1 mg/
kg) or imipramine (0.5 mg/kg) may be administered
intravenously and the tests repeated.16,38 Atropine sulfate,
which blocks muscarinic cholinergic activity, can allevi-
ate cataplectic attacks for as long as 3 hours.38,60 Imipra-
mine, which blocks the reuptake of norepinephrine,
thereby enhancing noradrenergic activity, alleviates cat-
aplectic attacks for as long as 45 minutes.38 Electrodiag-
nostic procedures, including electromyography, EEG,
and recordings of eye movement, have also been used
to document narcolepsy.17,59
Narcolepsy must be distinguished from disorders as-
sociated with acute collapse, including seizures, syn-
cope, myasthenia gravis, hypokalemia, Addison’s dis-
ease, and other metabolic disorders.8,16 Characteristic
signs of cataplexy as well as normal findings on physical
examination, neurologic examination (during normal
period), blood chemistries, and electrocardiography al-
low the distinction of narcolepsy from other disorders
that cause episodic weakness or acute collapse.15,16 Nar-
colepsy can be distinguished from seizures in general by
the clinical signs, history of attacks elicited by excite-
ment, and testing procedures discussed previously. Cat-
aplexy is not associated with tonic rigidity or excessive
salivation, defecation, and/or urination.15 Swallowing
and cough reflexes as well as respiratory and ocular
muscle functions are intact in narcoleptic animals.15,16
Clinical signs in animals with myasthenia gravis will
most likely improve with the administration of the pe-
ripherally acting cholinesterase inhibitors edrophonium
PHYSOSTIGMINE SALICYLATE ■ METHYLPHENIDATE ■ IMIPRAMINE
Compendium July 1999
chloride or neostigmine.16 Because edrophonium chlo-
ride and neostigmine do not cross the blood–brain bar-
rier (except at very high dosages), their effects on nar-
coleptic animals should be negligible.
TREATMENT
Therapeutic intervention in the treatment of nar-
colepsy in humans is aimed primarily at controlling ex-
cessive sleepiness and cataplexy. In veterinary medicine,
the primary therapeutic intervention is aimed at con-
trolling cataplexy.16 Although excessive sleepiness has
been reported in narcoleptic dogs, the impact of this
component of narcolepsy in dogs is less than that in
humans.
In humans, excessive daytime sleepiness is treated
most frequently with stimulants (e.g., methylphenidate,
methamphetamine, dextroamphetamine, and pemo-
line) that cause the release of catecholamines (dopa-
mine, epinephrine, and norepinephrine).1 It is now be-
lieved that enhanced dopamine activity, rather than
enhanced norepinephrine activity, accounts for the ben-
eficial effect of stimulants in treating excessive daytime
sleepiness. 1 Stimulants are generally less effective
against cataplexy unless used at a high enough dose to
influence noradrenergic activity.1
In veterinary medicine, methylphenidate (0.25 mg/
kg orally once daily) has been shown to have short-term
anticataplectic effects in certain patients.8,15,17,38 In addi-
tion, dextroamphetamine was used to treat narcolepsy
in a long-haired dachshund that was unresponsive to the
tricyclic antidepressant imipramine.61 Treatment was
discontinued, however, because of undesirable behav-
ioral effects (e.g., excessive sniffing of the ground, desire
to climb into inaccessible spaces, hyperactivity, complete
refusal of food).61
The most commonly used medications for the treat-
ment of cataplexy in both human and veterinary medi-
cine are the tricyclic antidepressants (Figure 3).1,62 The
anticataplectic activity of these agents has been posi-
tively correlated to adrenergic reuptake inhibition.1,63
In human medicine, imipramine, protriptyline, and
clomipramine are the most commonly used anticata-
plectic agents.1 In veterinary medicine, imipramine (0.5
to 1.0 mg/kg orally every 8 hours16,38,59,64) has been used
successfully in the long-term treatment of cataplexy.
Protriptyline (10 mg orally once daily) has been used to
treat hypersomnia in a Labrador retriever.65
Other tricyclic antidepressants used to treat behav-
ioral disorders in companion animals, including ami-
triptyline, trimipramine, clomipramine, and the des-
methyl metabolites desipramine and nortriptyline, may
prove useful in the treatment of cataplexy.1,66 Serotoner-
gic reuptake blockers, such as clomipramine and fluoxe-
Compendium July 1999 20TH ANNIVERSARY Small Animal/Exotics

tine, are believed to mediate their anticat-

aplectic effects via their active desmethyl
metabolites, which are more potent for
adrenergic reuptake inhibition.1,63
Potential side effects of the tricyclic an-
tidepressants reported in humans pre-
dominantly relate to their anticholinergic
activity and include constipation, urinary
retention, tachycardia and other arrhyth-
mias, dry mouth, anorexia, sweating,
drowsiness, and impotence.1,8 The most
common side effects reported in dogs in-
clude gastrointestinal distress, increased
appetite, and tachycardia.66 In addition,
hyperactivity, ataxia, vomiting, behavioral
changes, mydriasis, tremors, seizures,
lethargy, bradycardia, hepatotoxicity, and
death have all been reported in animals Figure 3—The predominant mechanisms of action of potentially valuable thera-
that ingested toxic amounts of tricyclic peutic agents for cataplexy. (1) Amphetamines: The release of the neurotransmit-
antidepressants.67 Typical therapeutic dos- ter is enhanced. (2 ) Tricyclic antidepressants: The reuptake of the neurotransmit-
ages of tricyclic antidepressants fall in the ter into the nerve terminal is decreased, thereby increasing the availability of
range of 2 to 4 mg/kg/day, often divided neurotransmitter for receptor binding. (3 ) Monoamine oxidase (MAO) inhibitors:
and given twice daily (e.g., 1 to 2 mg/kg The metabolism of the neurotransmitter is prevented, thereby increasing the
every 12 hours).66,67 Accidental ingestion amount of neurotransmitter available for packaging into synaptic vesicles. (4 ) α1-
of amounts exceeding 15 mg/kg are con- Agonists: Receptors on the postsynaptic membrane are directly stimulated. (5 ) α2-
sidered life threatening.67 High dosages of Antagonists: Autoreceptors on the presynaptic membrane are inhibited, thereby
tricyclic antidepressants have been impli- enhancing neurotransmitter release (α2-agonists: stimulation of autoreceptors on
66 the presynaptic membrane inhibits the release of neurotransmitter).1,62 (COMT =
cated in euthyroid sick syndrome. catechol-O-methyltransferase; L-dopa = levodopa; NE = norepinephrine.)
Tricyclic antidepressants are contraindi-
cated in animals with severe, uncon-
trolled cardiac arrhythmias and urinary retention.66 may prove to be beneficial in the future.
Routine blood screening and a cardiovascular evalua- The enzyme MAO-A preferentially metabolizes nor-
tion, including electrocardiography, should be evaluat- epinephrine and/or serotonin; MAO-B preferentially
ed before and periodically after the initiation of thera- metabolizes dopamine.1 The reversible MAO-A in-
py. Reported electrocardiographic abnormalities with hibitors brofaromine and moclobemide (8 to 16 mg/kg
tricyclic antidepressants include flattened T waves, pro- orally) have been used in the research setting to de-
longed QT intervals, and depressed ST segment.66 crease cataplexy without noticeable side effects in
Anticholinergic compounds have been unsuccessful in dogs.1,68 Selegiline (2 mg/kg orally), an irreversible in-
treating narcolepsy, partly because of the side effects re- hibitor of MAO-B used to treat Parkinson’s disease in
lated to their administration. Anticholinergics reduce humans and cognitive dysfunction in old dogs, also has
cataplexy through a central effect, but high doses are effective anticataplectic activity in dogs in the research
needed (e.g., 0.1 mg/kg intravenous atropine) and lead setting.1,66,68,69 The anticataplectic effects of selegiline
1
to a high degree of tachycardia, mydriasis, and sedation. are thought to be mediated by its metabolism to am-
Other therapies that may be important in the future phetamine and methamphetamine rather than its inhi-
include new monoamine oxidase (MAO) inhibitors, bition of MAO-B.1 Mild side effects of selegiline re-
precursors of neurotransmitters, more selective mono- ported in humans include dry mouth, headaches, and
amine agonists and antagonists, and the development insomnia.1
of selective M2 cholinergic antagonists with good pene- Dietary restriction of foods containing sympathomi-
tration into the central nervous system.1 First-generation metic amines (e.g., cheese, bananas, pickled and smoked
MAO inhibitors, although successful in treating nar- fish, fermented sausages) are not as extensive with the
colepsy, were shown to have a poor safety margin and new MAO inhibitors as with the original MAO inhib-
clinical use was discontinued.1 The development of itors unless higher dosages are required.1 The long-term
new MAO inhibitors selective for MAO-A or MAO-B safety of MAO inhibitors is still unknown; their use in

ANTICHOLINERGIC COMPOUNDS ■ MAO INHIBITORS ■ SELEGILINE

Small Animal/Exotics 20TH ANNIVERSARY Compendium July 1999

veterinary medicine for treating narcolepsy must be care- REFERENCES

fully assessed because of studies indicating an increased 1. Nishino S, Mignot E: Pharmacological aspects of human
sensitivity to these compounds in narcoleptic dogs and canine narcolepsy. Prog Neurobiol 52:27–78, 1997.
compared with normal animals.17,68 2. Aldrich MS: Sleep-related spells associated with parasomnias
and narcolepsy. Semin Neurol 15:194–202, 1995.
Because cataplectic attacks are generally not con- 3. Aldrich MS: Narcolepsy. Neurology 42:34–43, 1992.
sidered life threatening, the goal of therapy is to reduce 4. Nishino S, Tafti M, Sampathkumaran R, et al: Circadian
the frequency and duration of attacks.16 Completely distribution of rest/activity in narcoleptic and control dogs:
eliminating attacks may require dangerously high levels Assessment with ambulatory activity monitoring. J Sleep Res
of drugs with the risk of 6:120–127, 1997.
potentially serious side ef- 5. Kaitin KI, Kilduff TS, Dement WC: Sleep fragmentation in
ENDIU genetically narcoleptic dogs. Sleep 9:116–119, 1986.
MP fects.16 Owners should be
M’

20th

CO

6. Lucas EA, Foutz AS, Mitler MM, et al: Multiple sleep laten-
S

9 - 1
9 9 9
warned that abrupt with- cy test in normal and narcoleptic canines. Soc Neurosci Abst
1 9 7

ANNIVERSARY drawal of medication can 4:451, 1978.

lead to increased cataplexy 7. Mitler MM, Dement WC: Sleep studies on canine narcolep-

A LookBack or status cataplecticus.1
Narcolepsy, a Greek word
meaning “seized by
somnolence,” was first described
in humans as early as 1672
and in domesticated animals in
the early 1970s. Major
advances have been made in
understanding the
pathophysiology of narcolepsy,
particularly over the past 20
years. Among the factors
contributing to these advances
have been the establishment of a
narcoleptic canine colony in the
late 1970s. Studies conducted
in these animals continue to be
instrumental in elucidating
the neuroanatomic,
neurophysiologic, and
neurochemical alterations seen
in narcoleptic patients. These
dogs also play a pivotal role in
the development of safe, effective
pharmacologic agents to be used
in the treatment of narcolepsy
in both humans and
domesticated animals.
CONCLUSION
Cataplexy is the major
clinical sign of narcolepsy
in domesticated animals
and is thought to be relat-
ed to hypersensitivity to
cholinergic stimulation and
hypoactivity of noradren-
ergic neurons. The role of
dopamine in cataplexy is
still under investigation;
however, hypoactivity of
the dopaminergic system
is believed to play an im-
portant role in hypersom-
nolence associated with
narcolepsy. Therapy for
cataplexy currently in-
volves enhancing nor-
adrenergic activity with
tricyclic antidepressants.
Further studies are needed
to clarify the underlying
neuronal mechanisms in-
volved in narcolepsy and
to develop more selective
therapeutic agents with
fewer side effects.
ACKNOWLEDGMENTS
The author thanks Mrs.
Carol Williams, Depart-
ment of Biomedical Sci-
ences, School of Veteri-
nary Medicine, Tuskegee
University, for editing the
manuscript.
sy: Pattern and cycle comparisons between affected and nor-
mal dogs. Electroencephalogr Clin Neurophysiol 43:691–699,
1977.
8. Shell L: Sleep disorders, in Ettinger SJ, Feldman EC (eds):
Textbook of Veterinary Internal Medicine. Philadelphia, WB
Saunders Co, 1995, pp 157–158.
9. Lunn DP, Cuddon PA, Shaftoe S, Archer RM: Familial oc-
currence of narcolepsy in miniature horses. Equine Vet J 25:
483–487, 1993.
10. Dreifuss FE, Flynn DV: Narcolepsy in a horse. JAVMA
184:131–132, 1984.
11. Strain GM, Olcott BM, Archer RM, McClintock BK: Nar-
colepsy in a Brahman bull. JAVMA 185:538–541, 1984.
12. Sweeney CR, Hendricks JC, Beech J, Morrison AR: Nar-
colepsy in a horse. JAVMA 183:126–128, 1983.
13. Katherman AE: A comparative review of canine and human
narcolepsy. Compend Contin Educ Pract Vet 2(10):818–822,
1980.
14. Knecht CD, Oliver JE, Redding R, et al: Narcolepsy in a
dog and a cat. JAVMA 162:1052–1053, 1973.
15. Chrisman CL: Problems in Small Animal Neurology, ed 2.
Philadelphia, Lea & Febiger, 1991, pp 223–225.
16. Foutz AS, Mitler MM, Dement WC: Narcolepsy. Vet Clin
North Am Small Anim Pract 10:65–80, 1980.
17. Baker TL, Mitler MM, Foutz AS, Dement WC: Diagnosis
and treatment of narcolepsy in animals, in Kirk RW (ed):
Current Veterinary Therapy VIII. Small Animal Practice.
Philadelphia, WB Saunders Co, 1983, pp 755–759.
18. Riehl J, Nishino S, Cederberg R, et al: Development of cata-
plexy in genetically narcoleptic Dobermans. Exper Neurol
152:292–302, 1998.
19. Wauquier A, Verheyen JL, Van Den Broeck WAE, Janssen
PAJ: Visual and computer-based analysis of 24 h sleep-wak-
ing patterns in the dog. Electroencephalogr Clin Neurophys
46:33–48, 1979.
20. Macquet P: Positron emission tomography studies of sleep and
sleep disorders. J Neurol 244 (4)(Suppl 1):S23–S28, 1997.
21. Burt AM: Textbook of Neuroanatomy. Philadelphia, WB
Saunders Co, 1993, pp 474–478.
22. Jones BE: Paradoxical sleep and its chemical/structural sub-
strates in the brain. Neuroscience 40:637–656, 1991.
23. Hobson JA: Sleep and dreaming. J Neurosci 10:371–382,
1990.
24. Hendricks JC, Morrison AR: Normal and abnormal sleep in
mammals. JAVMA 178:121–126, 1981.

GOAL OF THERAPY ■ MEDICATION WITHDRAWAL

Compendium July 1999 20TH ANNIVERSARY
25. Jones BE, Yang TZ: The efferent projections from the retic-
ular formation and the locus coeruleus studied by antero-
grade and retrograde axonal transport in the rat. J Comp
Neurol 242:56–92, 1985.
26. Jones BE, Moore RY: Catecholamine-containing neurons of
the nucleus locus coeruleus in the cat. J Comp Neurol 157:
43–52, 1974.
27. Steriade M: Basic mechanisms of sleep generation. Neurology
42:9–18, 1992.
28. Steriade M, Datta S, Paré D, et al: Neuronal activities in
brain-stem cholinergic nuclei related to tonic activation pro-
cesses in thalamocortical systems. J Neurosci 10:2541–2559,
1990.
29. Rye DB: Contributions of the pedunculopontine region to
normal and altered REM sleep. Sleep 20:757–788, 1997.
30. Mitler MM, Dement WC: Cataplexy-like behavior in cats
after microinjection of carbachol in pontine reticular forma-
tion. Brain Res 68:335–343, 1974.
31. Jones BE: Immunohistochemical study of choline acetyl-
transferase-immunoreactive processes and cells innervating
the pontomedullary reticular formation in the rat. J Comp
Neurol 295:485–514, 1990.
32. Sakai K: Neurons responsible for paradoxical sleep, in
Wauquier A, Gaillard JM, Monti JM, Radulovaki M (eds):
Sleep: Neurotransmitters and Neuromodulators. New York,
Raven, 1985, pp 29–42.
33. Jones BE, Beaudet A: Distribution of acetylcholine and cate-
cholamine neurons in the cat brainstem: A choline acetyl-
transferase and tyrosine hydroxylase immunohistochemical
study. J Comp Neurol 261:15–32, 1987.
34. Dement WC, Carskadon M, Ley R: The prevalence of nar-
colepsy II. Sleep Res 2:147, 1973.
35. Guilleminault C, Mignot E, Grumet FC: Familial patterns
of narcolepsy. Lancet 2:1376–1379, 1989.
36. Bassetti C, Aldrich MS: Narcolepsy. Neurol Clin 14:545–
571, 1996.
37. Kessler S, Guilleminault C, Dement W: A family study of
50 REM narcoleptics. Acta Neurol Scand 50:503–512, 1974.
38. Braund KG: Clinical Syndromes in Veterinary Neurology, ed
2. St. Louis, Mosby, 1994, pp 196–198.
39. Foutz AS, Mitler MM, Cavalli-Sforza L, Dement WC: Ge-
netic factors in canine narcolepsy. Sleep Res 1:412–413,
1979.
40. Baker T, Foutz A, Neyman V, Dement W: Canine model of
narcolepsy: Genetic and developmental determinants. Exp
Neurol 75:729–742, 1982.
41. Reid MS, Tafti M, Geary JN, et al: Cholinergic mechanisms
in canine narcolepsy—I. Modulation of cataplexy via local
drug administration into the pontine reticular formation.
Neuroscience 59:511–522, 1994.
42. Reid MS, Tafti M, Geary JN, et al: Cholinergic mechanisms
in canine narcolepsy—II. Acetylcholine release in the pon-
tine reticular formation is enhanced during cataplexy. Neuro-
science 59:523–530, 1994.
43. Nishino S, Tafti M, Reid MS, et al: Muscle atonia is trig-
gered by cholinergic stimulation of the basal forebrain: Im-
plication for the pathophysiology of narcolepsy. J Neurosci
15:4806–4814, 1995.
44. Nishino S, Reid MS, Dement WC, Mignot E: Neurophar-
Small Animal/Exotics
macology and neurochemistry of canine narcolepsy. Sleep
17:S84–S92, 1994.
45. Nishino S, Haak L, Shepherd H, et al: Effects of central al-
pha-2 adrenergic compounds on canine narcolepsy, a disor-
der of rapid eye movement sleep. J Pharmacol Expl Ther
253:1145–1152, 1990.
46. Mignot E, Nishino S, Hunt Sharp LE, et al: Heterozygosity
of the canarc-1 locus can confer susceptibility for narcolepsy:
Induction of cataplexy in heterozygous asymptomatic dogs
after administration of a combination of drugs acting on
monoaminergic and cholinergic systems. J Neurosci 13:
1057–1064, 1993.
47. Nishino S, Mao J, Sampathkumaran R, et al: Differential ef-
fects of dopaminergic and noradrenergic uptake inhibitors
on EEG arousal and cataplexy of narcoleptic canines. Sleep
Res 25:317, 1996.
48. Kilduff T, Bowersox SS, Kaitan KI, et al: Muscarinic cholin-
ergic receptors and the canine model of narcolepsy. Sleep
9:102–107, 1986.
49. Boehme R, Baker T, Mefford I, et al: Narcolepsy: Choliner-
gic receptor changes in an animal model. Life Sci 34:1825–
1828, 1984.
50. Mignot E, Guilleminault C, Bowersox S, et al: Effects of α1
adrenoreceptor blockade with prazosin in canine narcolepsy.
Brain Res 444:184–188, 1988.
51. Fruhstorfer B, Mignot E, Bowersox S, et al: Canine nar-
colepsy is associated with an elevated number of α2 receptors
in the locus coeruleus. Brain Res 500:209–214, 1989.
52. Bowersox SS, Kilduff T, Faull K, et al: Brain dopamine re-
ceptor levels elevated in canine narcolepsy. Brain Res 402:
44–48, 1987.
53. Guilleminault C, Heinzer R, Mignot E, Black J: Investiga-
tions into the neurologic basis of narcolepsy. Neurology 50:
S8–S15, 1998.
54. Carlander B, Eliaou JF, Billard M: Autoimmune hypothesis
in narcolepsy. Neurophysiol Clin 23:15–22, 1993.
55. Mignot E, Tafti M, Dement WC, Grumet FC: Narcolepsy
and immunity. Adv Neuroimmunol 5:23–37, 1995.
56. Mignot E, Wang C, Rattazzi C, et al: Genetic linkage of au-
tosomal recessive canine narcolepsy with an immunoglobu-
lin µ chain switch-like segment. Proc Natl Acad Sci USA
88:3475–3478, 1991.
57. Tafti M, Nishino S, Aldrich MS, et al: Major histocompati-
bility class II molecules in the CNS: Increased microglial ex-
pression at the onset of narcolepsy in canine model. J Neu-
rosci 16:4588–4595, 1996.
58. Tafti M, Nishino S, Dement WC, Mignot E: Narcolepsy is
associated with increased microglial expression of MHC
class II molecules. Sleep Res 24A:372, 1995.
59. Oliver JE, Lorenz MD: Handbook of Veterinary Neurology,
ed 2. Philadelphia, WB Saunders Co, 1993, pp 308–309.
60. Hendricks JC, Hughes C: Treatment of cataplexy in a dog
with narcolepsy JAVMA 194:791–792, 1989.
61. Van Heerden J, Eckersley GN: Narcolepsy in a long-haired
dachshund. J S Afr Vet Assoc 60:151–153, 1989.
62. Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of
Neuropharmacology, ed 7. New York, Oxford University
Press, 1996, pp 282–285.
63. Nishino S, Arrigoni J, Shelton J, et al: Desmethyl metabo-
Small Animal/Exotics 20TH ANNIVERSARY
lites of serotonergic uptake inhibitors are more potent for
suppressing canine cataplexy than their parent compounds.
Sleep 16:706–712, 1993.
64. Mitler MM, Soave O, Dement WC: Narcolepsy in seven
dogs. JAVMA 168:1036–1038, 1976.
65. Shores A, Redding RW: Narcoleptic hypersomnia syndrome
responsive to protriptyline in a Labrador retriever. JAAHA
23:455–458, 1987.
66. Overall KL: Pharmacologic treatments for behavior prob-
lems. Vet Clin North Am Small Anim Pract 27:637–664,
1997.
67. Johnson LR: Tricyclic antidepressant toxicosis. Vet Clin
North Am Small Anim Pract 20:393–403, 1990.
Compendium July 1999
68. Nishino S, Arrigoni J, Kanbayashi T, et al: Comparative ef-
fects of MAO-a and MAO-b selective inhibitors on canine
cataplexy. Sleep Res 25:315, 1996.
69. Milgram NW, Ivy GO, Head E, et al: The effect of L-de-
prenyl on behavior, cognitive function, and biogenic amines
in the dog. Neurochem Res 18:1211–1219, 1993.
About the Author
Dr. Coleman is affiliated with the Department of Biomedi-
cal Sciences, School of Veterinary Medicine, Tuskegee
University, Tuskegee, Alabama.