Merrill M. Mitler

Cataplectic-like behavior in cats after micro-injections of carbachol in pontine reticular formation

There has been considerable work with focal injections of cholinergic compounds in the brain. Early work by Hernandez-Peon et al. 11, Mazzuchelli-O’Flaherty et al. 16, Cordeau et al. 4, George et al. 8, and Baxter1 suggests that cholinergic stimulation of the brain can induce sleep, REM sleep or motor inhibition akin to that seen in human cataplexy. Since the narcolepsy-cataplexy syndrome in humans is wide-spread 5,7 and has recently attracted much attention6,19, these sleep and motor inhibitory effects are of particular interest. An experimentally producible animal model of narcolepsy-cataplexy would be of use in evaluating treatments for cataplexy. To this end, an animal model of narcolepsy-cataplexy should show one or more of the following behaviors:

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.

Canine model of narcolepsy: Genetic and developmental determinants

Abstract Genetic and developmental factors were investigated in 101 cases of canine narcoleps-cataplexy syndrome. An experimental breeding program documented a probable autosomal recessive mode of inheritance in two dog breeds, Doberman pinschers and Labrador retrievers, and in crosses between those breeds. Age of onset of cataplexy and severity of symptoms were remarkably similar in 73 subjects with the genetically transmitted form of narcolepsy. Efforts to demonstrate genetic factors by breeding affected poodles and beagles were unsuccessful. Furthermore, a positive family history could not be documented in these animals or in narcoleptic dogs of 13 other breeds. Both age of onset and severity of symptoms were highly variable within this population. We suggest there may be multiple etiologies in canine narcolepsy syndrome: (i) inheritance via a single autosomal recessive gene, which appears to be identical in at least two unrelated dog breeds; (ii) nongenetic mechanisms which may include developmental or traumatic accidents. Preliminary findings of parallel neurochemical studies in narcoleptic dogs indicate distinct abnormalities in central neurotransmitter concentration and turnover. We theorize that these neurochemical abnormalities may result from inherited disorders of synthesis and/or metabolism which are present from birth or from nongenetic neurochemical abnormalities appearing later in life. The observation that symptom characteristics are identical in all affected dogs suggests that a common neurochemical disorder may underlie both genetic and nongenetic variations of the disease.

Sleep studies on canine narcolepsy: Pattern and cycle comparisons between affected and normal dogs☆

Two narcoleptic and 2 normal poodle or mixed poodle dogs were polygraphically monitored for 48 h with one narcoleptic and one normal monitored concurrently. Data were categorized by 15-sec epochs into wakefulness, light sleep, slow wave sleep, REM sleep, cataplexy (immobility preceded by wakefulness with partial or complete electromyographic quiescence and pronounced theta activity from subcortical leads), and atonia with no theta (15-30 sec periods like cataplexy but without theta). In narcoleptics we could see no gross differences between the polygraphic records of cataplexy and those of REM sleep; scoring distinctions between the two states depended on the antecedent state. Results indicated that narcoleptic dogs do not differ from normals with respect to percent of time spent in wakefulness (39.8% vs. 42.6%), light sleep (16.2% vs. 18.4%), or slow wave sleep (27.2% vs. 28.0%). Narcoleptic dogs spent slightly less time than normals in REM sleep (6.9% vs. 11.1%) and spend 9.1% and 0.8% of the recording time in cataplexy and atonia with no theta respectively. Normal dogs presented neither of these pathological states.

Narcolepsy-cataplexy in a female dog

Narcolepsy in human beings is a life-long illness afflicting 100,000–150,000 Americans. No current treatment for this neurological disorder is satisfactory and a definitive approach to the disease requires an animal model of narcolepsy. This report summarizes data on a female toy poodle which has a canine form of narcolepsy-cataplexy. At approximately 4 mo of age, the dog presented cataplectic attacks. Physical examination disclosed no systemic factors to account for such atonic episodes. Observation indicated that attacks were frequently partial, involving only the neck musculature and hind legs. However, such attacks could develop into complete cataplexy, causing postural collapse and areflexia, although extrinsic eye muscles and the muscles of respiration were spared. Presentation of food, water, or a plaything were the most frequent elicitors of attacks. During 41 hr of EEG, EOG, and EMG monitoring in conjunction with behavioral observation, the dog exhibited normal polygraphic wakefulness, slow-wave sleep and REM sleep. Unambiguous sleep onset REM periods and cataplectic attacks were also observed. These pathological manifestations are analogous to those characteristic of human narcolepsy. The diagnosis of canine narcolepsy was further confirmed by two negative trials with neostigmine (ruling out myasthenia) and two positive trials with imipramine (cataplexy in human narcolepsy responds to imipramine treatment). The dog will be bred either with a littermate or a similarly afflicted male in an attempt to produce a population of afflicted dogs.

Sleep and activity rhythms in mice: a description of circadian patterns and unexpected disruptions in sleep.

Studies on daily and circadian rhythms in wheel running and electrographically defined wakefulness, NREM sleep, and REM sleep in M. musculus were done to gather data on the temporal distribution of activity and sleep. Generally, peaks in NREM and sleep tended to coincide and to alternate with the coincident peaks of wakefulness and wheel running. However, during the active phase of the circadian wheel running cycle some NREM and REM sleep did occur; conversely, during its rest phase, wakefulness was often present. The most striking finding was that in mice with clearly entrained or free-running activity onsets, the circadian peak-through patterns in wakefulness, NREM, and REM sleep were not always distinct--they could be damped and/or polyphasic. Several explanations of these phenomena are considered.

Sleep cycle organization in narcoleptic and normal dogs.

Abstract The normal sleep-wake patterns of four narcoleptic and four normal dogs were recorded electrographically for 48 hours in a laboratory setting. The amount of the various stages of vigilance (wake, light slow wave sleep, deep slow wave sleep and REM sleep) were similar for both sets of dogs except that narcoleptic dogs has significantly less REM sleep and had an additional state scored as cataplexy. Mean episode durations and the number of episodes per 48 hr were not significantly different except that narcoleptic dogs had fewer REM episodes and a trend toward more waking episodes. There was a significant difference in the state progression between normal and narcoleptic dogs before and after REM episodes. Narcoleptic dogs had an increase in LSWS and a decrease in DSWS during the last 5 min before REM sleep onset in comparison to the reverse pattern in controls. In the stages following REM there was a marked elevation of wakefulness in narcoleptic dogs. These data support the notion that narcolepsy is a sleep disorder characterized by a disruption of the normal sleep-wake cycle. These results parallel similar findings in humans and provide strong evidence that this disease entity is similar in man and dog.

The effects of parachlorophenylalanine on the mating behavior of male rats

Abstract Four studies are presented on the effects of parachlorophenylalanine (PCPA) on the mounting behavior of male rats. The first study found that PCPA alone and in combination with either pargyline or testosterone increased the tendency for male rats to mount other males. The other three studies strongly indicated that PCPA alone can increase the frequency of heterosexual mounting and copulation in male rats.

Sleep and serotonin in two strains of Mus musculus.

Abstract Two strains of Mus musculus , C57BL/10J and BALB/CJ, were studied in an attempt to check for any naturally occurring correlation between sleep and brain serotonin. The C57BL/10J compared with the BALB/CJ had more slow wave sleep throughout the day and particularly during hours of darkness. During peak sleep periods, C57BL/10J also had more REM sleep. At three different times of the day (1200, 1600, and 0400 hr) neurochemical assays were done on brain stem and cerebral cortex for tryptophan and serotonin levels and for tryptophan hydroxylase activity. An inspection of the ordering of means for strains suggested that the greater amount of slow wave sleep for C57BL/10J was paralleled by higher brain stem and cortex tryptophan levels, higher cortex tryptophan hydroxylase activity, and higher cortex serotonin levels. An inspection of temporal trends across strain and time of day suggested that slow wave sleep may vary negatively with brain stem tryptophan hydroxylase activity, brain stem serotonin level, and cortex tryptophan level. While no simple sleep-serotonin relationship obtained, because of such trends the data were interpreted as being generally consistent with the hypothesis of an active serotonergic sleep inducing mechanism in brain.