Autoradiographic studies of post-mortem human narcoleptic brain

Aldrich,; Hollingsworth, Zane R.; Penney, JB

doi:10.1016/s0987-7053(05)80281-3

Cited by 35 publications

(11 citation statements)

References 36 publications

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“…Narcoleptic canines have elevated levels of dopaminergic and noradrenergic receptors in the amygdala, brainstem, and basal forebrain (Mefford et al, 1983;Kilduff et al, 1986). Similar changes are present in human narcoleptics (Aldrich et al, 1992(Aldrich et al, , 1993(Aldrich et al, , 1994. Cholinergic stimulation of the basal forebrain triggers cataplexy in narcoleptic, but not in control canines (Nishino et al, 1995).…”

Section: Discussionmentioning

confidence: 93%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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Narcolepsy is a lifelong illness characterized by persistent sleepiness, hypnagogic hallucinations, and episodes of motor paralysis called cataplexy. We have tested the hypothesis that a transient neurodegenerative process is linked to symptom onset. Using the amino-cupric silver stain on brain sections from canine narcoleptics, we found elevated levels of axonal degeneration in the amygdala, basal forebrain (including the nucleus of the diagonal band, substantia innominata, and preoptic region), entopeduncular nucleus, and medial septal region. Reactive neuronal somata, an indicator of neuronal pathology, were found in the ventral amygdala. Axonal degeneration was maximal at 2-4 months of age. The number of reactive cells was maximal at 1 month of age. These degenerative changes precede or coincide with symptom onset. The forebrain degeneration that we have observed can explain the major symptoms of narcolepsy.Key words: narcolepsy; REM sleep; amygdala; basal forebrain; canine; amino-cupric silver; degeneration; cataplexy Narcolepsy, which occurs at a rate of 0.2-1.6 per thousand (Aldrich, 1990;Hublin et al., 1994), was first recognized 118 years ago by Gélineau (Passouant, 1976). Its symptoms include excessive daytime sleepiness, hypnagogic hallucinations (dream-like mentation in waking), REM sleep at sleep onset, cataplexy (a loss of muscle tone in waking, usually triggered by sudden, strong emotions), and sleep paralysis (an inability to move at sleep onset or awakening) . Narcolepsy has been reported in horses, cattle, and dogs (Mitler et al., 1976; Strain et al., 1984). C anine narcoleptics have been intensively studied. Like human narcoleptics, they are excessively sleepy and have cataplexy. Symptoms in canine and human narcoleptics display a similar response to pharmacological agents Nishino and Mignot, 1997). The cause of narcolepsy is unknown.Narcolepsy is not a progressive disease, in that once symptoms have become f ully established, in both human and canine narcoleptics, they do not become worse (or markedly better) with age. This suggests that narcolepsy may be caused by a transient degenerative process. E xaminations of postmortem tissue in human narcoleptics have not produced consistent evidence for degenerative changes. However, symptom onset is typically 50 or more years before autopsy, a sufficient interval for the removal of any debris resulting from degeneration at the time of disease onset. The age of onset of canine narcolepsy is between 1 and 4 months. In the current study, we have used the amino-cupric stain (de Olmos et al., 1994), an extremely sensitive indicator of degenerating neurons and axons (Switzer, 1991;Fix et al., 1996), to test the hypothesis that narcolepsy onset is linked to neuronal degeneration. MATERIALS AND METHODSEighteen Doberman pinscher dogs, nine narcoleptic and nine age-and breed-matched controls (four male narcoleptics and seven male controls), from six narcoleptic and five normal litters ranging from 1 to 8 months of age were used (Table 1). Control and narcole...

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Section: Discussionmentioning

confidence: 93%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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“…This degeneration peaks at 1–4 months of age and is maximal in limbic regions, which do not have Hcrt cell somas. It has been reported that the Hcrt-r2 mutation in the dog, the Hcrt null mutation in the mouse, and the loss of Hcrt cells in human narcolepsy cause changes in the concentration of a number of receptor types, including receptors for dopamine and acetylcholine, and also cause abnormities in monoamine metabolism (Aldrich et al, 1993;Fruhstorfer et al, 1989;Kilduff et al, 1986;Mefford et al, 1983;Mishima et al, 2008;Mori et al, 2010;Nishino et al, 1994;Nishino and Mignot, 1997;Nishino and Sagawa, 2010). Mice lacking Hcrt receptors have elevated levels of choline acetyltransferase, vesicular acetylcholine transporter and the high affinity choline transporter in the laterodorsal tegmental nucleus (Kalogiannis et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Role of the Hypocretin (Orexin) Receptor 2 (Hcrt-r2) in the Regulation of Hypocretin Level and Cataplexy

Wu¹,

Nienhuis²,

Maidment³

et al. 2011

J. Neurosci.

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Hypocretin receptor-2 (Hcrt-r2) mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans, yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effect of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2 mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug induced cataplexy by virtue of its longterm effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans.

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“…Studies of narcoleptic dogs and narcoleptic humans have found a marked upregulation of cholinergic (ACh) receptors in the medial mesopontine region (Boehme et al, 1984;Kilduff et al, 1986;Aldrich et al, 1990). Injection of cholinergic agonists in the medial mesopontine reticular formation regions of intact cats produces a loss of muscle tone without loss of consciousness that resembles cataplexy (Mitler and Dement, 1974) or a REM sleep-like state (George et al, 1964;Van Dongen, 1978;Katayama et al, 1984;Baghdoyan et al, 1987) depending on the exact injection site.…”

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confidence: 99%

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

et al. 1992

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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)

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Autoradiographic studies of post-mortem human narcoleptic brain

Cited by 35 publications

References 36 publications

Neuronal Degeneration in Canine Narcolepsy

Neuronal Degeneration in Canine Narcolepsy

Role of the Hypocretin (Orexin) Receptor 2 (Hcrt-r2) in the Regulation of Hypocretin Level and Cataplexy

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

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