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At least 631 records · Page 35Linked to original sources
PubMed2002

Cessation of activity in red nucleus neurons during stimulation of the medial medulla in decerebrate rats.

The pontine oral reticular nucleus, gigantocellular reticular nucleus (Gi) and dorsal paragigantocellular nucleus (DPGi) of the medulla are key elements of a brainstem-reticulospinal inhibitory system that participates in rapid eye movement (REM) sleep atonia. Our recent study has shown that excitation of these brainstem nuclei in decerebrate rats inhibits locus coeruleus cells and the midbrain locomotor region neurons related to muscle tone facilitation. In the present study we have examined the influences of electrical and chemical stimulation of Gi and DPGi inhibitory sites on the activity of neurons located in the magnocellular part of the red nucleus (RMC), a cell group that participates in both the tonic and phasic regulation of motor output. A total of 192 RMC neurons were recorded in precollicular-premammillary decerebrate rats with muscle rigidity and induced locomotion. Thirty-three RMC neurons were identified antidromically as rubrospinal (RMC-spinal) cells by stimulation of the contralateral dorsolateral funiculus at the L2 level. A total of 141 RMC neurons (88.7 %) and all RMC-spinal neurons were inhibited during electrical stimulation of Gi and DPGi inhibitory sites. This cessation of activity was correlated with bilateral muscle atonia or blockage of locomotion. Six RMC cells (3.8 %) were excited (224 +/- 50 %, n = 6, minimum = 98, maximum = 410, P < 0.05) and 11 cells (7 %) gave no response to Gi and DPGi stimulation. Microinjections of kainic acid (100 microM, 0.2 microl) into Gi and DPGi inhibitory sites, previously identified by electrical stimulation, produced a short-latency (35 +/- 3.5 s, n = 11) decrease of rigid hindlimb muscle tone and inhibition of all tested RMC (n = 7) and RMC-spinal (n = 5) neurons. These results, combined with our recent published data, suggest that inhibition of motor function during activation of the brainstem inhibitory system is related to both the descending inhibition of spinal motoneurons and suppression of activity in supraspinal motor facilitatory systems. These two mechanisms acting synergistically may cause generalized motor inhibition during REM sleep and cataplexy.

Animals↗
PubMed2004

GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier.

gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V(max) = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.

Adjuvants, Anesthesia↗
PubMed1998

Novel chromosomal abberation in a patient with a unique sleep disorder.

A 45 year old woman presenting with periodic hypersomnia for 17 years is reported on. She would sleep for three weeks followed by the same period awake. Polysomnography in the somnolent period disclosed an excess of total sleeping time with remarkably increased stage 1, 3/4, and REM sleep, without cataplexy or sleep paralysis. HLA typing was incompatible with narcolepsy or REM sleep behavioural disorder. Her chromosomes showed premature centromere division with chromatid puffing in areas of constitutive heterochromatin, which is exclusively found in the syndrome of infants termed Roberts' syndrome/SC phocomelia. Other laboratory findings were not normal. It is suggested that the present case is a novel sleep disorder related to a unique chromosomal aberration.

Centromere↗
PubMed1998

Breeding history of the Stanford colony of narcoleptic dogs.

Narcolepsy is a disabling sleep disorder of unknown aetiology. In humans, the disease is mostly sporadic, with a few familial cases having been reported. In 1973 a sporadic case of narcolepsy was reported in a poodle, and in 1975 familial cases of narcolepsy occurred in dobermanns. As with human narcoleptics, these narcoleptic dogs exhibited excessive daytime sleepiness and cataplexy. A colony of narcoleptic dogs was established at Stanford University in 1976 to study the pathophysiology of the disease. Between 1976 and 1995, a total of 669 animals of various breeds were born, of which 487 survived. Dobermanns accounted for 78 per cent of the total. The narcolepsy genotype in dobermanns had no significant influence on puppy mortality rate (numbers of stillborn and survival rate). The sex, maternal parity or the age of the sire or dam had no significant effect. The percentage of stillborn puppies increased from 6.1 per cent in outbred litters to 15.4 per cent in inbred litters (P = 0.10). Birth season also had a significant effect, and the highest survival rate (P = 0.02), and the lowest percentage of stillborn puppies (P = 0.09) occurred between April and June.

Animals↗
PubMed2003

Narcolepsy in a hypocretin/orexin-deficient chihuahua.

A two-year-old male chihuahua suffered attacks of muscle weakness and immobility, although it had no family history of paroxysmal attacks. No neurological or blood biochemical abnormalities were recorded when it was first examined. The attacks were typically elicited by stimulation, such as feeding, and a case of sporadic narcolepsy-cataplexy was therefore suspected. Treatment orally three times a day with 1 mg/kg imipramine, was effective in reducing the attacks. The concentration of hypocretin-1/orexin A in the dog's cerebrospinal fluid was less than 80 pg/ml (22.5 pmol/litre), compared with normal canine levels of 250 to 350 pg/ml (70.0 to 98.3 pmol/litre), supporting a diagnosis of hypocretin-deficient narcolepsy.

Adrenergic Uptake Inhibitors↗
PubMed2001

To eat or to sleep? Orexin in the regulation of feeding and wakefulness.

Orexin-A and orexin-B are neuropeptides originally identified as endogenous ligands for two orphan G-protein-coupled receptors. Orexin neuropeptides (also known as hypocretins) are produced by a small group of neurons in the lateral hypothalamic and perifornical areas, a region classically implicated in the control of mammalian feeding behavior. Orexin neurons project throughout the central nervous system (CNS) to nuclei known to be important in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis, and autonomic regulation. orexin mRNA expression is upregulated by fasting and insulin-induced hypoglycemia. C-fos expression in orexin neurons, an indicator of neuronal activation, is positively correlated with wakefulness and negatively correlated with rapid eye movement (REM) and non-REM sleep states. Intracerebroventricular administration of orexins has been shown to significantly increase food consumption, wakefulness, and locomotor activity in rodent models. Conversely, an orexin receptor antagonist inhibits food consumption. Targeted disruption of the orexin gene in mice produces a syndrome remarkably similar to human and canine narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and other pathological manifestations of the intrusion of REM sleep-related features into wakefulness. Furthermore, orexin knockout mice are hypophagic compared with weight and age-matched littermates, suggesting a role in modulating energy metabolism. These findings suggest that the orexin neuropeptide system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions.

Animals↗
PubMed2004

Hypocretin (orexin): role in normal behavior and neuropathology.

The hypocretins (Hcrts, also known as orexins) are two peptides, both synthesized by a small group of neurons, most of which are in the lateral hypothalamic and perifornical regions of the hypothalamus. The hypothalamic Hcrt system directly and strongly innervates and potently excites noradrenergic, dopaminergic, serotonergic, histaminergic, and cholinergic neurons. Hcrt also has a major role in modulating the release of glutamate and other amino acid transmitters. Behavioral investigations have revealed that Hcrt is released at high levels in active waking and rapid eye movement (REM) sleep and at minimal levels in non-REM sleep. Hcrt release in waking is increased markedly during periods of increased motor activity relative to levels in quiet, alert waking. Evidence for a role for Hcrt in food intake regulation is inconsistent. I hypothesize that Hcrt's major role is to facilitate motor activity tonically and phasically in association with motivated behaviors and to coordinate this facilitation with the activation of attentional and sensory systems. Degeneration of Hcrt neurons or genetic mutations that prevent the normal synthesis of Hcrt or of its receptors causes human and animal narcolepsy. Narcolepsy is characterized by an impaired ability to maintain alertness for long periods and by sudden losses of muscle tone (cataplexy). Administration of Hcrt can reverse symptoms of narcolepsy in animals, may be effective in treating human narcolepsy, and may affect a broad range of motivated behaviors.

Animals↗
PubMed2003

Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism.

Hypocretin-1 and -2 (Hcrt-1 and -2, also called orexin-A and -B) are newly identified neuropeptides synthesized by hypothalamic neurons. Defects in the Hcrt system underlie the sleep disorder narcolepsy, which is characterized by sleep fragmentation and the involuntary loss of muscle tone called cataplexy. Hcrt neurons project to multiple brain regions including cranial and spinal motor nuclei. In vitro studies suggest that Hcrt application can modulate presynaptic glutamate release. Together these observations suggest that Hcrt can affect motor output and that glutamatergic processes may be involved. We addressed these issues in decerebrate cats by applying Hcrt-1 and -2 into the trigeminal motor nucleus to determine whether these ligands alter masseter muscle activity and by pretreating the trigeminal motor nucleus with a N-methyl-d-aspartate (NMDA) antagonist to determine if glutamatergic pathways are involved in the transduction of the Hcrt signal. We found that Hcrt-1 and -2 microinjections into the trigeminal motor nucleus increased ipsilateral masseter muscle tone in a dose-dependent manner. We also found that Hcrt application into the hypoglossal motor nucleus increases genioglossus muscle activity. Pretreatment with a NMDA antagonist (d-(-)-2-amino-phosphonovaleric acid) abolished the excitatory response of the masseter muscle to Hcrt-1 application; however, pretreatment with methysergide, a serotonin antagonist had no effect. These studies are the first to demonstrate that Hcrt causes the excitation of motoneurons and that functional NMDA receptors are required for this response. We suggest that Hcrt regulates motor control processes and that this regulation is mediated by glutamate release in the trigeminal motor nucleus.

2-Amino-5-phosphonovalerate↗
PubMed2002

Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla.

Orexins/hypocretins are synthesized in neurons of the perifornical, dorsomedial, lateral, and posterior hypothalamus. A loss of hypocretin neurons has been found in human narcolepsy, which is characterized by sudden loss of muscle tone, called cataplexy, and sleepiness. The normal functional role of these neurons, however, is unclear. The medioventral medullary region, including gigantocellular reticular nucleus, alpha (GiA) and ventral (GiV) parts, participates in the induction of locomotion and muscle tone facilitation in decerebrate animals and receives moderate orexinergic innervation. In the present study, we have examined the role of orexin-A (OX-A) in muscle tone control using microinjections (50 microM, 0.3 microl) into the GiA and GiV sites in decerebrate rats. OX-A microinjections into GiA sites, previously identified by electrical stimulation as facilitating hindlimb muscle tone bilaterally, produced a bilateral increase of muscle tone in the same muscles. Bilateral lidocaine microinjections (4%, 0.3 microl) into the dorsolateral mesopontine reticular formation decreased muscle rigidity and blocked muscle tone facilitation produced by OX-A microinjections into the GiA sites. The activity of cells related to muscle rigidity, located in the pedunculopontine tegmental nucleus and adjacent reticular formation, was correlated positively with the extent of hindlimb muscle tone facilitation after medullary OX-A microinjections. OX-A microinjections into GiV sites were less effective in muscle tone facilitation, although these sites produced a muscle tone increase during electrical stimulation. In contrast, OX-A microinjections into the gigantocellular nucleus (Gi) sites and dorsal paragigantocellular nucleus (DPGi) sites, previously identified by electrical stimulation as inhibitory points, produced bilateral hindlimb muscle atonia. We propose that the medioventral medullary region is one of the brain stem target for OX-A modulation of muscle tone. Facilitation of muscle tone after OX-A microinjections into this region is linked to activation of intrinsic reticular cells, causing excitation of midbrain and pontine neurons participating in muscle tone facilitation through an ascending pathway. Moreover, our results suggest that OX-A may also regulate the activity of medullary neurons participating in muscle tone suppression. Loss of OX function may, therefore, disturb both muscle tone facilitatory and inhibitory processes at the medullary level.

Anesthetics, Local↗
PubMed2000

Reduced leptin levels in human narcolepsy.

Recently, hypocretins have been implicated in the pathophysiology of narcolepsy, a sleep disorder characterized particularly by the occurrence of excessive daytime sleepiness and cataplexy. Hypocretins, which stimulate food intake, have been reported to be absent in the cerebrospinal fluid (CSF) of the majority of patients suffering from narcolepsy. Because these patients also display an increased body mass index (BMI), it has been suggested that disturbances in metabolism and food intake regulation may be present. To further investigate these presumed alterations, we studied the production of leptin, a fat-cell-derived hormone signaling to the brain the size of the adipose tissue. We measured the levels of leptin in serum and CSF from 15 narcoleptic patients and compared the results to those from age-, sex- and BMI-matched control groups of depressive patients and patients suffering from a noninflammatory neurological disorder. Compared to both control groups, leptin levels in serum, but not in the CSF, were significantly reduced in narcoleptic patients by more than 50%. These results support the hypothesis that human narcolepsy is accompanied by complex alterations of the regulation of food intake and metabolism. The significance of these alterations for the core symptomatology of narcolepsy should be a target of future research.

Major Depressive Disorder↗
PubMed1991

Clinical aspects of Niemann-Pick type C disease in the adult.

Niemann-Pick type C disease diagnosed in adult neurology departments may be infantile or juvenile forms with prolonged life span or forms starting at adolescence or adulthood. The evolution is generally slower compared to the infantile cases. Psychomotor retardation is practically constant. Cerebellar ataxia and extrapyramidal manifestations are often found in opposition to pyramidal symptoms. Supranuclear ophthalmoplegia with a down-gaze failure is nearly constant. Cataplexy and other types of seizures may be found during the evolution of the disease. In some cases a psychosis may be the only manifestation for several years; the treatment by psychotropic drugs raises the question of a superimposition of a drug-induced lipidosis. Hepatosplenomegaly is often discrete, contrary to infantile cases. Foam cells or sea-blue histiocytes are a general feature of the disease. Although the primary defect is unknown, diagnosis must be confirmed by the defect in cholesterol esterification from exogenous cholesterol.

Cerebellar Ataxia↗
PubMed1985

Efficacy of trazodone in narcolepsy.

A 25-year-old man with narcolepsy and cataplexy experienced partial relief of symptomatology following administration of methylphenidate. Moreover, the latter caused extreme agitation and aggression. However, administration of the antidepressant agent trazodone resulted in almost complete alleviation of the narcoleptic and cataplectic attacks within 48 h after initiation of therapy. Trazodone, a novel antidepressant agent may be useful in the long-term management of individuals suffering from narcolepsy.

Adult↗
PubMed1990

Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology?

Response to pharmacologic treatments may identify groups of disorders with a common pathophysiology. The authors applied a treatment-response model, based on four classes of antidepressants (tricyclic types, monoamine oxidase inhibitors, serotonin uptake inhibitors, and atypical agents), to the medical literature. The model identified eight disorders that may share a pathophysiologic abnormality: major depression, bulimia, panic disorder, obsessive-compulsive disorder, attention deficit disorder with hyperactivity, cataplexy, migraine, and irritable bowel syndrome. Phenomenologic and family studies support this grouping. If the model is validated, this family of disorders, which the authors term "affective spectrum disorder," would represent one of the most prevalent diseases in the population.

Antidepressive Agents↗
PubMed2003

The influence of gender and food on the pharmacokinetics of sodium oxybate oral solution in healthy subjects.

Sodium oxybate (Xyrem; gamma-hydroxybutyrate) oral solution was recently approved in the United States for the treatment of cataplexy in patients with narcolepsy. Two single-center, randomized, open-label studies in healthy volunteers receiving single oral 4.5-g doses of sodium oxybate evaluated effects of (1) gender on oxybate pharmacokinetics and (2) food on its oral bioavailability. In the latter study, one dose was administered after an overnight fast, another after a high-fat meal; 1 week separated treatments. Sodium oxybate pharmacokinetics was not significantly different between sexes. However, food significantly altered the bioavailability of oxybate by decreasing mean peak plasma concentration, increasing median time-to-peak concentration, and decreasing the area under the plasma concentration-time curve. Food did not affect elimination and urinary excretion of unchanged drug. No dose adjustment of sodium oxybate based on sex is indicated. Although significant food effects were observed, these are minimized in patients by the nocturnal dosing of sodium oxybate hours after the evening meal at a consistent time interval following food ingestion.

Administration, Oral↗
PubMed2001

ApoE polymorphisms in narcolepsy.

BACKGROUND: Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. METHODS: To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. RESULTS: The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. CONCLUSION: Our results exclude the ApoE4 allele as a major risk factor for narcolepsy.

Journal Article↗
PubMed2003

Alteration of the striatal dopaminergic system in human narcolepsy.

Striatal D2/D3 dopaminergic receptors have been proposed to play a role in cataplexy. The authors studied the striatal presynaptic dopamine transporter and postsynaptic D2-receptors in seven patients with narcolepsy and seven control subjects using [123I](N)-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane and [123I](S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl)benzamide SPECT. D2-receptor binding was elevated in narcolepsy (p = 0.017) and correlated with the frequency of cataplectic and sleep attacks (R > or = 0.844, p < or = 0.017). The human striatal dopaminergic system is altered in vivo in narcolepsy/cataplexy.

Aged↗
PubMed2003

Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation.

The authors report the case of a 60-year-old man with acromegaly, who developed narcolepsy 2 weeks after completing radiotherapy for a pituitary adenoma. Cataplexy and sleepiness were predominant symptoms. Onset of narcolepsy is unusual at this age and the temporal relationship following radiotherapy suggests this treatment was implicated. His CSF hypocretin levels were normal, indicating other factors may be important in his narcolepsy.

Acromegaly↗
PubMed1987

Terguride, a mixed dopamine agonist-antagonist, in animal models of Parkinson's disease.

Terguride, an analogue of lisuride, decreased locomotor activity, produced cataplexy, and blocked apomorphine-induced stereotypic behavior. It did not induce stereotypies in rodents or emesis in dogs. However, in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, terguride produced contralateral rotation. Terguride bound to D-2 striatal dopamine receptors. Terguride has both agonist and antagonist actions at striatal dopamine receptors, but chronic administration did not produce behavioral supersensitivity. These pharmacologic properties differ from those of other antiparkinsonian agents; terguride may be effective for the chronic treatment of Parkinson's disease.

Amphetamine↗