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PubMed1981

An etiology of narcolepsy-cataplexy and a proposed cataplexy neuromechanism.

Narcolepsy-cataplexy is an idiopathic sleep disorder that reflects a complex neuropathology. Surveys and physiological investigations indicate that genetic and stress factors are involved in its onset and that stress is associated with symptomatic fluctuations and exacerbations of its clinical course. This paper summarizes the literature regarding the evolution, characteristics and treatment of the disorder. A comprehensive etiology is advanced, integrating neurophysiological and psychological factors specific to narcolepsy-cataplexy with recent advances in blood pressure regulation. Moreover, a testable neuromechanism of cataplexy is proposed, based on longitudinal effects of chronic drowsiness, the strong hypnogenic effect obtained by carotid sinus stimulation, an experimental animal model of narcolepsy-cataplexy, the adaptive characteristics of baroreceptors and, finally, the interconnections between CNS sleep and blood pressure regulators of the brain stem. Through better understanding of the causes and mechanisms of narcolepsy-cataplexy, more effective treatments and preventive measures can be developed, high risk populations identified, and, perhaps, a cure found. Suggestions for future physiological and epidemiological research are made.

Cataplexy↗
PubMed1997

HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.

Narcolepsy is a sleep disorder associated with HLA DR15 (DR2) and DQB1*0602. We HLA typed 509 patients enrolled in a clinical trial for the drug modafinil and analyzed the results in relation to cataplexy, a symptom of narcolepsy characterized by muscle weakness triggered by emotions. The patients were either subjects with cataplexy who had a mean sleep latency (SL) of less than 8 minutes and two or more sleep onset rapid eye movement (REM) periods (SOREMPs) during a multiple sleep latency test, or narcoleptic patients without cataplexy but with a mean SL shorter than 5 minutes and two or more SOREMPs. The respective values of DRB1*15 (DR2) and DQB1*0602 as markers for narcolepsy were first compared in different ethnic groups and in patients with and without cataplexy. DQB1*0602 was found to be a more sensitive marker for narcolepsy than DRB1*15 across all ethnic groups. DQB1*0602 frequency was strikingly higher in patients with cataplexy versus patients without cataplexy (76.1% in 421 patients versus 40.9% in 88 patients). Positivity was highest in patients with severe cataplexy (94.8%) and progressively decreased to 54.2% in patients with the mildest cataplexy. A voluntary 50-item questionnaire focusing on cataplexy was also analyzed in 212 of the 509 HLA-typed patients. Subjects with definite cataplexy as observed by an experienced clinician were more frequently HLA DQB1*0602-positive than those with doubtful cataplexy, and the manifestations of cataplexy were clinically more typical in DQB1*0602-positive patients. These results show that the HLA association is as tight as previously reported (85-95%) when cataplexy is clinically typical or severe. We also found that patients with mild, atypical, or no cataplexy have a significantly increased DQB1*0602 frequency (40-60%) in comparison with ethnically matched controls (24%). These results could be explained by increased disease heterogeneity in the noncataplexy group or by a direct effect of the HLA DQB1*0602 genotype on the clinical expression of narcolepsy.

Adolescent↗
PubMed1994

Cholinergic mechanisms in canine narcolepsy--I. Modulation of cataplexy via local drug administration into the pontine reticular formation.

Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.

Analysis of Variance↗
PubMed1989

Heart rate and blood pressure changes during sleep-waking cycles and cataplexy in narcoleptic dogs.

Cataplexy is the abrupt loss of muscle tone experienced by narcoleptics. It is usually precipitated by strong emotions or athletic activity. It has been hypothesized that cardiovascular variables have a role in the triggering of cataplexy. In the present study, we have utilized the narcoleptic canine model to directly investigate changes in heart rate and blood pressure in relation to cataplectic episodes. We found that heart rate increased 18% on average in the 20 s preceding cataplexy onset and then fell during cataplexy. Thus, from a cardiovascular standpoint, cataplexy can be subdivided into two very different periods, the cataplexy onset period with very high and declining heart rate, and the period greater than or equal to 10 s after onset, with greatly reduced heart rate. Heart rate at cataplexy onset was significantly higher than heart rate in rapid-eye-movement (REM) sleep, non-REM sleep, and quiet waking. Blood pressure did not markedly change before the onset of spontaneous cataplexies but decreased significantly during cataplexy. Although blood pressure increases did not precede spontaneous cataplexies, sudden increases in blood pressure, induced pharmacologically or by obstruction of the descending aorta, triggered cataplexy in the most severely affected subjects. A hypothesized role for cataplexy as a homeostatic reflex, triggered by interactions between blood flow, central chemoreceptors, and atonia control mechanisms in the medial medulla, is discussed.

Animals↗
PubMed1994

Cholinergic regulation of cataplexy in canine narcolepsy in the pontine reticular formation is mediated by M2 muscarinic receptors.

Both rapid eye movement sleep and cataplexy in the narcoleptic canine have been shown to increase after both systemic and local administration of cholinergic agonists in the pontine reticular formation. Furthermore, binding studies indicate an increase in the number of M2 muscarinic receptors in the pontine reticular formation of narcoleptic canines. In the present study we have investigated the receptor subtypes involved in mediating the cholinergic stimulation of cataplexy, as defined by brief periods of hypotonia induced by emotions, within the pontine reticular formation of narcoleptic canines. Specific cholinergic and monoaminergic agonists and antagonists, and excitatory or inhibitory amino-acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of narcoleptic canines, and cataplexy was monitored using the Food-Elicited Cataplexy Test and recordings of electroencephalogram, electrooculogram and electromyogram. In narcoleptic canines, bilateral perfusion with oxotremorine (M2 muscarinic) (10(-5)-10(-3) M) in the pontine reticular formation produced a dose-dependent increase in cataplexy, which reached complete muscle atonia (status cataplecticus) during the highest concentration. In control canines bilateral perfusion with oxotremorine (10(-5)-10(-3) M) did not produce any cataplectic attacks, but did produce muscle atonia after the highest concentration. Bilateral perfusion with either McN-A-343 (M1 muscarinic) or nicotine (both 10(-5)-10(-3) M) did not have any effect on cataplexy in either narcoleptic or control canines. The increase in cataplexy in narcoleptic canines produced by local perfusion with carbachol (10(-4) M) followed by equimolar perfusion with a muscarinic antagonist was rapidly reversed by atropine (muscarinic) and gallamine (M2 muscarinic), partially reversed by 4-DAMP (M3/M1 muscarinic) and completely unaffected by pirenzepine (M1 muscarinic). Bilateral perfusion with excitatory, glutamatergic receptor agonists N-methyl-D-aspartate, AMPA (both at 10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effect on cataplexy, whereas bilateral perfusion with the inhibitory GABAergic receptor agonist muscimol (10(-4)-10(-3) M) produced a moderate increase in cataplexy in the narcoleptic canines. Bilateral perfusion with numerous monoaminergic compounds, BHT-920 (alpha-2 agonist), yohimbine (alpha-2 antagonist), propranolol (beta antagonist) and prazosin (alpha-1 antagonist), did not have any effect on cataplexy. These findings demonstrate that cholinergic regulation of cataplexy in the narcoleptic canine at the level of the pontine reticular formation is mediated by M2, and possibly M3, muscarinic receptors. The effects of muscimol indicate that the stimulation of cataplexy might be elicited by local neuronal inhibition.

Animals↗
PubMed1996

Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine.

Cataplexy in the narcoleptic canine may be modulated by systemic administration of monoaminergic compounds. In the present study, we have investigated the effects of monoaminergic drugs on cataplexy in narcoleptic canines when perfused locally via microdialysis probes in the amygdala, globus pallidus/putamen, basal forebrain, pontine reticular formation and ventral tegmental area of narcoleptic and control Doberman pinchers. Cataplexy was quantified using the Food-Elicited Cataplexy Test and analyzed by electroencephalogram, electroculogram and electromyogram. Local perfusion with the monoaminergic agonist quinpirole, 7-OH-DPAT and BHT-920, into the ventral tegmental area produced a dose-dependent increase in cataplexy without significantly reducing basal muscle tone. Perfusion with the antagonist raclopride in the same structure produced a moderate reduction in cataplexy. Local perfusion with quinpirole, 7-OH-DPAT and BHT-920 into the globus pallidus/putamen also produced an increase, while raclopride produced a decrease, in cataplexy in narcoleptic canines. In control animals, none of the above drugs produced cataplexy or muscle atonia when perfused into either the ventral tegmental area or the globus pallidus/putamen. Other monoaminergic drugs tested in these two brain areas; prazosin, yohimbine, amphetamine, SKF 38393 and SCH 23390 had no effects on cataplexy. Local perfusion with each of the above listed drugs had no effect on cataplexy in any of the other brain regions examined. These findings show that cataplexy may be regulated by D2/D3 dopaminergic receptors in the ventral tegmental area and perhaps the globus pallidus/ putamen. It is suggested that neurons in the mesolimbic dopamine system of narcoleptics are hypersensitive to dopaminergic autoreceptor agonists.

Amygdala↗
PubMed1992

Activity of medial mesopontine units during cataplexy and sleep-waking states in the narcoleptic dog.

Narcolepsy has been hypothesized to be a disease of rapid eye movement (REM) sleep. According to this hypothesis, cataplexy is a result of the triggering during waking of the mechanism that normally serves to suppress muscle tone in REM sleep. REM sleep control mechanisms have been localized to the pons. Narcoleptic dogs have increased numbers of cholinergic receptors in the medial pons. These findings suggest that neurons mediating the triggering of cataplexy might be located in medial pontine regions. In the present study, this hypothesis has been investigated by recording the discharge of units in the medial mesopontine region of the narcoleptic dog. Unit activity was examined in the nucleus reticularis pontis oralis, caudalis, and central gray, with each cell being recorded during both cataplexy and sleep states. Maximal discharge rates were observed, in all of these regions, during active waking states (mean rate, 45.3/sec) and REM sleep (16.0/sec), with minimal discharge rates in non-REM sleep (8.3/sec). Unit discharge was reduced in cataplexy relative to precataplexy periods. Cataplexy discharge rates were 8.3/sec, 52% of the mean REM sleep rate. Cataplexy discharge rates were also significantly lower than those at REM sleep onset. Cataplexy discharge rates were comparable to rates in quiet waking and non-REM sleep. While medial mesopontine neurons discharge at high rates in REM sleep, they have little or no activity in cataplexy. We interpret the lack of activation of medial mesopontine units in cataplexy as indicating that the characteristic phasic motor activation of REM sleep does not occur in this state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Monoaminergic mechanisms and experimental cataplexy.

The effects of pharmacological alteration of the monoamine systems were investigated in a canine model of narcolepsy. Cataplexy was quantified in eight severely affected dogs by means of the food-elicited cataplexy test. The specific norepinephrine (NE) uptake blocker nisoxetine, and (to a much lesser extent) the specific serotonin (5-HT) uptake blocker fluoxetine, significantly suppressed cataplexy, as did the tricyclic antidepressants protriptyline, amitriptyline, and chlorimipramine. Thus, experimental cataplexy is suppressed more by inhibition of the uptake of NE than of 5-HT. Methylphenidate, the alpha-adrenoreceptor blocker clonidine, and the dopamine receptor blocker pimozide also suppressed cataplexy in dogs. The beta-adrenergic blocker propranolol, the fatty acid gamma-hydroxybutyrate, and the monoamine oxidase inhibitors clorgyline and pargyline had little or no effect. With one exception (pimozide), all the drugs that suppressed cataplexy are known to be potent suppressors of REM sleep. The suppression of cataplexy induced by nisoxetine or protriptyline was reversed by the anticholinesterase physostigmine, further supporting a postulated aminergic-cholinergic interaction in the mechanisms for cataplexy.

Animals↗
PubMed1999

Validation of a cataplexy questionnaire in 983 sleep-disorders patients.

Our goal was to validate a self-administered narcolepsy questionnaire focusing on cataplexy. Nine hundred and eight three consecutive subjects entering the Stanford Sleep Disorder Clinic completed the questionnaire. Clinic physicians reported on the presence or absence of "clear-cut" cataplexy. Responses to 51 cataplexy-related questionnaire items were compared between subjects with clear-cut cataplexy (n = 63) and all other patients (n = 920). As previously reported, a large portion of the non-narcoleptic population was found to experience muscle weakness with various intense emotions (1.8% to 18.0%) or athletic activities (26.2% to 28.8%). Factor analysis and Receiver Operating Characteristic Curve (ROC) analysis were used to determine the most predictive items for clear-cut cataplexy. Most strikingly, cataplexy was best differentiated from other types of muscle weakness when triggered by only three typical situations: "when hearing and telling a joke," "while laughing," or "when angry." Face or neck, rather than limbs, were also more specifically involved in clear-cut cataplexy. Other items, such as length of attacks, bilaterality, and alteration in consciousness, were poorly predictive. A simple decision tree was constructed to isolate high-(91.7%) and low-(0.6%) risk groups for cataplexy. This questionnaire will be used to increase diagnostic consistency across clinical centers, thus providing more homogenous subject pools for clinical and basic research studies.

Adolescent↗
PubMed1998

Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines.

Basal forebrain (BF) cholinergic regulation of cataplexy was investigated in narcoleptic canines. Specific cholinergic agonists and antagonists, and excitatory or inhibitory amino acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the BF of narcoleptic canines. Cataplexy was monitored using the food-elicited cataplexy test (FECT) and recordings of electroencephalogram, electrooculogram, and electromyogram. In narcoleptic canines, carbachol and oxotremorine (10(-5)-10(-3) M), but not McN-A-343 or nicotine (10(-4)-10(-3) M), produced a dose-dependent increase in cataplexy. In addition, N-methyl-d-aspartate (10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effects, while muscimol (10(-3) M) produced a weak (P < 0.10) increase in cataplexy. In control canines, carbachol (10(-5)-10(-3) M), but not oxotremorine (10(-4)-10(-3) M), produced muscle atonia after the highest concentration in one of three animals. Carbachol (10(-3) M)-induced cataplexy in narcoleptic canines was blocked by equimolar perfusion with the muscarinic antagonists atropine, gallamine, and 4-DAMP but not pirenzepine. These findings indicate that carbachol-stimulated cataplexy in the BF of narcoleptic canines is mediated by M2, and perhaps M3, muscarinic receptors. The release of acetylcholine in the BF was also examined during FECT and non-FECT behavioral stimulation in narcoleptic and control canines. A significant increase in acetylcholine release was found in both narcoleptic and control BF during FECT stimulation. In contrast, simple motor activity and feeding, approximating that which occurs during an FECT, did not affect acetylcholine release in the BF of narcoleptic canines. These findings indicate that BF acetylcholine release is enhanced during learned emotion/reward associated behaviors in canines.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1994

Cholinergic mechanisms in canine narcolepsy--II. Acetylcholine release in the pontine reticular formation is enhanced during cataplexy.

Cataplexy in the narcoleptic canine has been shown to increase after local administration of carbachol into the pontine reticular formation. Rapid eye movement sleep has also been shown to increase after local administration of carbachol in the pontine reticular formation, and furthermore, acetylcholine release in the pontine tegmentum was found to increase during rapid eye movement sleep in rats. Therefore, in the present study we have investigated acetylcholine release in the pontine reticular formation during cataplexy in narcoleptic canines. Extracellular acetylcholine levels were measured in the pontine reticular formation of freely moving narcoleptic and control Doberman pinschers using in vivo microdialysis probes. Cataplexy was induced by the Food-Elicited Cataplexy Test and monitored using recordings of electroencephalogram, electrooculogram and electromyogram. Basal levels of acetylcholine in the microdialysis perfusates were approximately 0.5 pmol/10 min in both control and narcoleptic canines. Local perfusion with tetrodotoxin (10(-5) M) or artificial cerebrospinal fluid without Ca2+ produced a decrease, while intravenous injections of physostigmine (0.05 mg/kg) produced an increase in acetylcholine levels, indicating that the levels of acetylcholine levels measured are derived from neuronal release. During cataplexy induced by the Food-Elicited Cataplexy Test, acetylcholine levels increased by approximately 50% after four consecutive tests in narcoleptic canines, but did not change after four consecutive tests in control canines. Motor activity and feeding behavior, similar to that occurring during a Food-Elicited Cataplexy Test, had no effect on acetylcholine levels in the narcoleptic canines.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

The effect of zimelidine, a serotonin-reuptake blocker, on cataplexy and daytime sleepiness of narcoleptic patients.

Narcolepsy is a neurological syndrome characterized by two major symptoms: excessive daytime sleepiness and cataplexy. Pharmacological and biochemical evidence support the hypothesis that dopaminergic mechanisms are involved in excessive daytime sleepiness. The pathophysiology of cataplexy and the action mechanisms of anticataplectic agents remain controversial issues. Cataplexy is usually controlled by tricyclic antidepressants, but these drugs interact with several central monoamine systems and also exert an anticholinergic effect. In the present study, zimelidine, a selective serotonin reuptake inhibitor without anticholinergic activity, was administered to 11 narcoleptic patients for 1-16 months. Cataplexy improved markedly in all patients, while no changes could be documented on excessive daytime sleepiness, either by self-report or polysomnographic nap recording. These results confirm the hypothesis that hypersomnolence and cataplexy are subject to different control mechanisms; support a serotoninergic, but not a cholinergic, theory of cataplexy; and suggest that selective serotonin reuptake inhibitors may be the treatment of choice for cataplexy.

Adult↗
PubMed1993

Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy.

We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.

Adrenergic alpha-Agonists↗
PubMed1998

Development of cataplexy in genetically narcoleptic Dobermans.

Forty-two genetically narcoleptic Doberman puppies [20 pure narcoleptic (N) puppies (from four narcoleptic x narcoleptic crosses) and 22 backcross narcoleptic (BN) puppies (from six narcoleptic x heterozygous crosses)] were systematically observed during the developmental period (4-24 weeks) to assess the age at onset and severity of cataplexy, a pathological manifestation of REM sleep atonia seen in narcolepsy. The mean age of onset of cataplexy was 9.69 +/- 1.15 weeks, with a median age of 7 weeks. The severity of cataplexy increased with age and reached a plateau at around 16-24 weeks. The effects of cross type (N vs BN) and sex on the development of cataplexy were analyzed. There was no difference in severity between N and BN puppies (P = 0.51). However, females had more severe cataplexy than males (P = 0.01), and this trend was preserved in five of the six litters that had both male and female puppies. These results suggest that the pathophysiological process in genetic canine narcolepsy emerges during the early developmental period and that it may involve a differential development in males and females. Furthermore, our results revealed that cataplexy onset corresponds to the emergence of adult-like REM sleep and to previously reported neuroanatomical and neurochemical abnormalities in canine narcolepsy.

Age of Onset↗
PubMed1996

Carbamazepine as a treatment for cataplexy.

Cataplexy is a common symptom associated with narcolepsy. We evaluated a 51-year-old female who developed symptoms of progressive daytime sleepiness with cataplexy. The diagnosis of narcolepsy was confirmed by overnight polysomnogram and was consistent with results of a multiple sleep latency study, and episodes of cataplexy were documented by video-EEG-EMG monitoring. Examination during a catapletic episode was significant for areflexia and paralysis. The frequency of cataplexy increased with fluoxetine, protriptyline and sertraline and the patient developed frank choreiform movements with protriptyline and sertraline. The cataplexy resolved following treatment with carbamazepine. We feel carbamazepine is a potential treatment for patients with refractory cataplexy.

Anticonvulsants↗
PubMed1995

Effect of 5-HT1A receptor agonists and antagonists on canine cataplexy.

Pharmacological studies using a canine model of narcolepsy have demonstrated that adrenergic rather than serotonergic or dopaminergic uptake inhibition is the primary mode of action of antidepressants on cataplexy, a pathological manifestation of rapid eye movement (REM) sleep atonia that occurs in narcolepsy. This result is in line with the known involvement of adrenergic systems in the regulation of REM sleep. However, the lack of anticataplectic effects of selective serotonergic compounds was puzzling as serotonergic neurons of the dorsal raphe nuclei are known to decrease activity during the REM sleep in a manner similar to the adrenergic neurons of the locus coeruleus. To further explore the role of serotonergic systems, we tested the effect on canine cataplexy of six 5-HT1A agonists and five 5-HT1A antagonists. Results indicate that 5-HT1A agonists significantly suppress cataplexy in correlation with their in vitro affinities to the canine central 5-HT1A receptors. Anticataplectic effects were, however, accompanied by various behavioral changes, such as flattened body posture, increased panting and agitation. In contrast, the selective 5-HT1A antagonist did not aggravate cataplexy, although a 5-HT1A antagonist was able to block the anticataplectic effect of a 5-HT1A agonist. These results suggest that the anticataplectic effects of 5-HT1A agonists are truly mediated by 5-HT1A receptor stimulation. It is, however, likely that anticataplectic effects occur due to the behavioral side effects rather than the direct involvement of this receptor subtype in the regulation of cataplexy. Further studies are therefore necessary to address the question of whether these 5-HT1A agonists hold promise in the pharmacological treatment of human cataplexy.

Animals↗
PubMed1995

Physiology of REM sleep, cataplexy, and sleep paralysis.

The main neural structures generating muscle atonia and other phenomena characteristic of REM sleep are present in dorsolateral portions of the pons in the brainstem. Occurrence of REM sleep and the NREM-REM sleep cycle are probably determined by a balance or interaction between the cholinergic and cholinoceptive REM sleep-on neuronal populations and the monoaminergic REM sleep-off neuronal population. Neural activities producing generalized muscle atonia in REM sleep originate mainly in dorsolateral portions of the pontine reticular formation, descend through the medulla and spinal cord, and inhibit the motoneurons in the brainstem and spinal cord, bringing about postural atonia. Cataplexy and sleep paralysis are pathological, dissociated manifestations of the generalized muscle atonia characteristic REM sleep. Cataplexy is triggered by emotional stimuli, probably through activation of the neural structure generating the muscle atonia of REM sleep. During long-lasting cataplectic attacks, narcoleptic humans often experience sleep paralysis and vivid hypnagogic hallucinations in the latter sleep state. Sleep paralysis is caused by the marked dissociation between level of alertness and muscle atonia that often occurs in SOREM sleep episodes. Frequent SOREM sleep episodes in narcoleptic humans and dogs may occur when some of the neural mechanisms producing wakefulness and/or NREM sleep that normally inhibit the occurrence of REM sleep are abnormally weak, or when neural mechanisms facilitating the occurrence of REM sleep are hypersensitive or hyperactive, or both. Both abnormalities may contribute to the occurrence of SOREM sleep episodes and sleep paralysis, and also to the emotional triggering of cataplexy. Frequent occurrence of SOREM sleep episodes seems to be prerequisite but not sufficient for the occurrence of cataplexy. Some additional neural activities induced by emotion also contribute by inhibiting and/or activating the disturbed neural mechanisms related to SOREM sleep episodes. These abnormalities in neural mechanisms probably involve hypersensitivity or hyperactivity of muscarinic cholinergic and/or cholinoceptive neuronal populations in the pontine and suprapontine structures, and/or abnormally decreased activity of noradrenergic or serotonergic neuronal populations in the pons and/or other brainstem structures. This last monoaminergic neuronal population probably has a gating or inhibiting effect upon the cholinergic and cholinoceptive neuronal populations related to the generation of generalized muscle atonia and REM sleep. In spite of many studies and published reports on REM sleep, as well as on cataplexy and sleep paralysis, we are still far from a complete understanding of the physiological mechanisms producing muscle atonia in REM sleep and of the pathophysiological mechanisms of cataplexy and sleep paralysis--though it is apparent that these mechanisms are closely related.

Animals↗
PubMed1991

Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.

Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

Animals↗