Chemelli R M, JT Willie et al.
(1999). "Narcolepsy in orexin knockout mice:
molecular genetics of sleep regulation." Cell
98(4): 437-51.... Neurons containing the
neuropeptide orexin (hypocretin) are located
exclusively in the lateral hypothalamus and send
axons to numerous regions throughout the central
nervous system, including the major nuclei
implicated in sleep regulation. Here, we report
that, by behavioral and electroencephalographic
criteria, orexin knockout mice exhibit a
phenotype strikingly similar to human narcolepsy
patients, as well as canarc-1 mutant dogs, the
only known monogenic model of narcolepsy.
Moreover, modafinil, an anti-narcoleptic drug
with ill-defined mechanisms of action, activates
orexin-containing neurons. We propose that
orexin regulates sleep/wakefulness states, and
that orexin knockout mice are a model of human
narcolepsy, a disorder characterized primarily
by rapid eye movement (REM) sleep
dysregulation.
de
Lecea L, TS Kilduff et al.
(1998). "The hypocretins: hypothalamus-specific
peptides with neuroexcitatory activity." Proc
Natl Acad Sci U S A 95(1): 322-7.... We describe
a hypothalamus-specific mRNA that encodes
preprohypocretin, the putative precursor of a
pair of peptides that share substantial amino
acid identities with the gut hormone secretin.
The hypocretin (Hcrt) protein products are
restricted to neuronal cell bodies of the dorsal
and lateral hypothalamic areas. The fibers of
these neurons are widespread throughout the
posterior hypothalamus and project to multiple
targets in other areas, including brainstem and
thalamus. Hcrt immunoreactivity is associated
with large granular vesicles at synapses. One of
the Hcrt peptides was excitatory when applied to
cultured, synaptically coupled hypothalamic
neurons, but not hippocampal neurons. These
observations suggest that the hypocretins
function within the CNS as
neurotransmitters.
Hagan J J, R A Leslie et al. (1999).
"Orexin A activates locus coeruleus cell firing
and increases arousal in the rat." Proc Natl
Acad Sci U S A 96(19): 10911-6.... The
localization of orexin neuropeptides in the
lateral hypothalamus has focused interest on
their role in ingestion. The orexigenic neurones
in the lateral hypothalamus, however, project
widely in the brain, and thus the physiological
role of orexins is likely to be complex. Here we
describe an investigation of the action of
orexin A in modulating the arousal state of rats
by using a combination of tissue localization
and electrophysiological and behavioral
techniques. We show that the brain region
receiving the densest innervation from
orexinergic nerves is the locus coeruleus, a key
modulator of attentional state, where
application of orexin A increases cell firing of
intrinsic noradrenergic neurones. Orexin A
increases arousal and locomotor activity and
modulates neuroendocrine function. The data
suggest that orexin A plays an important role in
orchestrating the sleep-wake cycle.
Hakansson M, L de Lecea et al.
(1999). "Leptin receptor- and
STAT3-immunoreactivities in hypocretin/orexin
neurones of the lateral hypothalamus." J
Neuroendocrinol 11(8): 653-63. ...
Hypocretins/orexins are recently characterized
peptides that are synthesized in neurones of the
lateral hypohalamus and stimulate food intake in
rats. To clarify whether leptin may interact
with hypocretin/orexin to reduce ingestive
behaviour, the presence of leptin
receptor-immunoreactivity in
hypocretin/orexin-containing neurones was
examined. Many leptin receptor-and
hypocretin/orexin-immunoreactive neurones were
demonstrated in the lateral hypothalamic area
and perifornical region. Both direct
double-labelling and elution-restaining methods
showed that leptin receptor-immunoreactivity was
present in the vast majority of
hypocretin/orexin-containing neurones.
Immunoreactivity for STAT3, a transcription
factor activated by leptin, was also
demonstrated in hypocretin/orexin-containing
neurones. Isolated hypocretin/orexin cell bodies
in the dorsal part of the lateral hypothalamic
area and the ventral perifornical region were
shown to contain immunoreactivity for galanin,
another peptide known to affect feeding. Galanin
neurones were also seen to contain leptin
receptor-and STAT3-immunoreactivity.
Melanin-concentrating hormone (MCH)-containing
neurones constituted a cell population within
the lateral hypothalamus distinct from the one
containing hypocretin/orexin-immunoreactivity,
as shown by elution-restaining methodology. The
presence of leptin receptor-and
STAT3-immunoreactivities in
hypocretin/orexin-containing neurones of the
lateral hypothalamus suggests that leptin may
directly regulate these hypothalamic neurones,
most likely via an inhibitory action on
hypocretin/orexin expression and/or secretion
resulting in reduced food intake.
Lin L, J. Faraco et al. (1999). "The
sleep disorder canine narcolepsy is caused by a
mutation in the hypocretin (orexin) receptor 2
gene." Cell 98(3): 365-76....Narcolepsy is a
disabling sleep disorder affecting humans and
animals. It is characterized by daytime
sleepiness, cataplexy, and striking transitions
from wakefulness into rapid eye movement (REM)
sleep. In this study, we used positional cloning
to identify an autosomal recessive mutation
responsible for this sleep disorder in a
well-established canine model. We have
determined that canine narcolepsy is caused by
disruption of the hypocretin (orexin) receptor 2
gene (Hcrtr2). This result identifies
hypocretins as major sleep-modulating
neurotransmitters and opens novel potential
therapeutic approaches for narcoleptic
patients.
Lubkin M and A Stricker-Krongrad
(1998). "Independent feeding and metabolic
actions of orexins in mice." Biochem Biophys Res
Commun 253(2): 241-5.... Orexin-A and orexin-B
(OX peptides) are two putative products of a
newly discovered secreted protein encoded by a
mRNA restricted to neuronal cell bodies of the
lateral hypothalamus (LH). Because the
activation of the LH can induce changes in
energy balance, we wanted to investigate the
actions of OX peptides on energy metabolism in
mice. We injected male C57BL/6J mice with
different doses (1, 3, and 10 nmol) of orexin-A
and orexin-B into the third ventricle (i3vt). A
single i3vt injection of orexin-A 3 h into the
light period slightly stimulated feeding at the
lowest dose only over the following 4 h (11 +/-
09 mg/mouse vs 80 +/- 13 mg/mouse, p < 0.05).
Orexin-B showed no effects at any dose. We
therefore investigated the effects of 3 nmol
orexin-A on energy utilization using indirect
calorimetry. Single i3vt injection 3 h after
light on, or just before dark onset, or in 4-h
fasted mice resulted in increases in the
metabolic rate. These effects were associated
with decreases or increases in the respiratory
quotient regarding the time of injection or the
underlying metabolic state of the mice. The
present findings provide direct evidence that OX
peptides are more likely to be involved in the
control of energy metabolism than of food intake
in mice.
Mignot
E (2001). "A commentary on the
neurobiology of the hypocretine/orexin system."
Neuropsychopharmacology 25(5 Suppl): S5-13...
hypocrtin/orexins are rapidly emerging as
functionally important neurotransmitters. Two
related neuropeptides (Hcrt-1/OXA, Hcrt-2/OXB)
encoded by the same precursor gene and two
G-protein coupled receptors (Hcrtr1/OXR1,
Hcrtr2/OXR2) are currently known.
hypocrtinee-containing cells are discretely
localized within the perifornical hypothalamus
but have widespread projections, with generally
excitatory postsynaptic effects. Dense
excitatory projections to all monoaminergic cell
groups have been reported. A major emerging
function for this system is likely to be the
regulation of sleep. Alterations in hypocretin
neurotransmission causes the sleep disorder
narcolepsy in mice, dogs and humans. Effects on
appetite, neuroendocrine and energy metabolism
regulation are also suggested by other studies.
hypocrétines are uniquely positioned to
link sleep, appetite and neuroendocrine control,
three behaviors of major importance in
psychiatry. The potential role of this system in
regulating the sleep cycle, modulating
wakefulness at selected circadian times and in
mediating the deleterious effects of sleep
deprivation is discussed.
Moore R Y, E A Abrahamson et al.
(2001). "The hypocretin neuron system: an
arousal system in the human brain." Arch Ital
Biol 139(3): 195-205... hypocretin are recently
discovered neuropeptides produced by a small
group of posterior hypothalamic neurons which
project widely over the neuroaxis. In this
study, we note that hypocretin neuron perikarya
in the human brain are localized to the
perifornical region of the posterior
hypothalamus, extending into the lateral
hypothalamus. These neurons lightly innervate
all areas of cerebral cortex studied in a
variable pattern with denser innervation of
association cortex than primary motor or sensory
cortex. There is a dense innervation of
hypothalamus, locus coeruleus, raphe nuclei,
midline thalamus and nucleus of the diagonal
band-nucleus basalis complex of the forebrain.
This pattern of projections from the
hypocrétinee neurons is compatible with
an important role in arousal and the maintenance
of the waking state.
Nishino S, B Ripley et al. (2000).
"Hypocretin (orexin) deficiency in human
narcolepsy." Lancet 355(9197): 39-40.
Alterations in the hypocretin receptor 2 and
preprohypocretin genes produce narcolepsy in
animal models. Hypocretin was undetectable in
seven out of nine people with narcolepsy,
indicating abnormal hypocretin
transmission.
Overeem S, E Mignot et al. (2001).
"Narcolepsy: clinical features, new
pathophysiologic insights, and future
perspectives." J Clin Neurophysiol 18(2):
78-105.... Narcolepsy is characterized by
excessive daytime sleepiness and abnormal
manifestations of rapid eye movement sleep such
as cataplexy. The authors review the clinical
features of narcolepsy, including epidemiology,
symptoms, diagnosis, and treatment, in detail.
Recent findings show that a loss of
hypocretin-producing neurons lies at the root of
the signs and symptoms of narcolepsy. The
authors review the current state of knowledge on
hypocretin anatomy, physiology, and function
with special emphasis on the research regarding
the hypocretin deficiency in narcolepsy, which
may also explain associated features of the
disorder, such as obesity. Lastly, they discuss
some future perspectives for research into the
pathophysiology of sleep/wake disorders, and the
potential impact of the established hypocretin
deficiency on the diagnosis and treatment of
narcolepsy.
Peyron C, J Faraco et al. (2000). "A
mutation in a case of early onset narcolepsy and
a generalized absence of hypocretin peptides in
human narcoleptic brains." Nat Med 6(9):
991-7... We explored the role of hypocretins in
human narcolepsy through histopathology of six
narcolepsy brains and mutation screening of
Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of
various human leukocyte antigen and family
history status. One Hcrt mutation, impairing
peptide trafficking and processing, was found in
a single case with early onset narcolepsy. In
situ hybridization of the perifornical area and
peptide radioimmunoassays indicated global loss
of hypocretins, without gliosis or signs of
inflammation in all human cases examined.
Although hypocretin loci do not contribute
significantly to genetic predisposition, most
cases of human narcolepsy are associated with a
deficient hypocretin system.
Sakurai T, A Amemiya et al. (1998).
"Orexins and orexin receptors: a family of
hypothalamic neuropeptides and G protein-coupled
receptors that regulate feeding behavior." Cell
92(4): 573-85... The hypothalamus plays a
central role in the integrated control of
feeding and energy homeostasis. We have
identified two novel neuropeptides, both derived
from the same precursor by proteolytic
processing, that bind and activate two closely
related (previously) orphan G protein-coupled
receptors. These peptides, termed orexin-A and
-B, have no significant structural similarities
to known families of regulatory peptides.
prepro-orexin mRNA and immunoreactive orexin-A
are localized in neurons within and around the
lateral and posterior hypothalamus in the adult
rat brain. When administered centrally to rats,
these peptides stimulate food consumption.
prepro-orexin mRNA level is up-regulated upon
fasting, suggesting a physiological role for the
peptides as mediators in the central feedback
mechanism that regulates feeding behavior.
Salin-Pascual
R, D Gerashchenko et al.
(2001).(version
intégral pdf) "Hypothalamic
regulation of sleep." Neuropsychopharmacology
25(5 Suppl): S21-7... The recent discovery
linking narcolepsy, a sleep disorder
characterized by very short REM sleep latency,
with a neuropeptide that regulates feeding and
energy metabolism, provides a way to understand
how several behaviors may be disrupted as a
result of a defect in this peptide. In this
chapter we review the evidence linking
hypocrétinee and sleep, including our own
studies, and propose that a defect in the
lateral hypothalamus that also involves the
hypocrétinee neurons is likely to produce
a disturbance in sleep, mood, appetite, and
rhythms.
Sato-Suzuki
I, I Kita, et al. (2002). "Cortical
arousal induced by microinjection of orexins
into the paraventricular nucleus of the rat."
Behav Brain Res 128(2): 169-77..
(version intégral
pdf) Orexin-A is a neuropeptide which has
been suggested to be involved in sleep and
arousal mechanisms. Orexin-A, for example,
stimulates arousal when administrated
intracerebroventricularly to rats. We attempted
to identify specific neural sites of orexin-A
and orexin-B action. Orexin-A and orexin-B were
microinjected into the medial parvocellular
subdivision of the paraventricular nucleus (PVN)
in anesthetized, spontaneously breathing rats,
and cortical arousal and yawning
responses were assessed. Cortical arousal
responses were monitored with the
electrocorticogram (ECoG), and yawning responses
were evaluated by monitoring intercostal
electromyograms as an index of inspiratory
activity and digastric electromyograms as an
indicator of mouth opening. We also measured
blood pressure and heart rate during yawning
responses, since yawning is accompanied by
changes in autonomic activity. Microinjection of
orexin-A into the PVN elicited an arousal shift
in the ECoG to lower voltage and faster rhythms.
This cortical arousal response was followed by a
single large inspiration with mouth opening,
i.e. a yawning response. On the other hand,
microinjection of orexin-B into the PVN elicited
an arousal shift in the ECoG without yawning
responses. These results demonstrate that an
orexin receptive site for triggering
arousal/yawning responses exists in the PVN, and
suggest that the PVN is involved in arousal
mechanisms
Huan ZL, WM Qu, et al. (2001).
"Arousal effect of orexin A depends on
activation of the histaminergic system." Proc
Natl Acad Sci U S A 98(17): 9965-70. : Orexin
neurons are exclusively localized in the lateral
hypothalamic area and project their fibers to
the entire central nervous system, including the
histaminergic tuberomammillary nucleus (TMN).
Dysfunction of the orexin system results in the
sleep disorder narcolepsy, but the role of
orexin in physiological sleep-wake regulation
and the mechanisms involved remain to be
elucidated. Here we provide several lines of
evidence that orexin A induces wakefulness by
means of the TMN and histamine H(1) receptor
(H1R). Perfusion of orexin A (5 and 25 pmol/min)
for 1 hr into the TMN of rats through a
microdialysis probe promptly increased
wakefulness for 2 hr after starting the
perfusion by 2.5- and 4-fold, respectively,
concomitant with a reduction in rapid eye
movement (REM) and non-REM sleep. Microdialysis
studies showed that application of orexin A to
the TMN increased histamine release from both
the medial preoptic area and the frontal cortex
by approximately 2-fold over the baseline for 80
to 160 min in a dose-dependent manner.
Furthermore, infusion of orexin A (1.5 pmol/min)
for 6 hr into the lateral ventricle of mice
produced a significant increase in wakefulness
during the 8 hr after starting infusion to the
same level as the wakefulness observed during
the active period in wild-type mice, but not at
all in H1R gene knockout mice. These findings
strongly indicate that the arousal effect of
orexin A depends on the activation of
histaminergic neurotransmission mediated by H1R.
