Posted by dove on November 4, 2004, at 9:08:24
I just read an interesting paper on Medscape :
http://www.medscape.com/viewarticle/491437_1The full article is really long, regarding narcolepsy, excessive daytime sleepiness and other sleep disorders. However, the most in depth findings relate back to disorders that have similarities with depressive (and depression related) symptoms and the monoaminergic and cholinergic systems. Which are what we all are looking at for relief. How these are all intertwined just amazes me. If anyone wants me to post the whole article, let me know.
Does anyone have ideas in regard to how the hypocretin system relates to and affects the monoaminergic and cholinergic systems, and what this might imply???
dove
"A series of studies have now shown that the hypocretin system is a major excitatory system that affects the activity of monoaminergic (dopamine, norepinephrine, serotonin, and histamine) and cholinergic systems with major effects on vigilance states.[80,81]"
Abstract:
Narcolepsy and Syndromes of Primary Excessive Daytime Somnolence
Posted 10/26/2004
Jed E. Black, M.D.; Stephen N. Brooks, M.D.; Seiji Nishino, M.D., Ph.D.
Abstract and Introduction
Abstract
Excessive daytime sleepiness (EDS) or somnolence is common in our patients and in society in general. The most common cause of EDS is "voluntary" sleep restriction. Other common causes include sleep-fragmenting disorders such as the obstructive sleep apnea syndrome. Somewhat less familiar to the clinician are EDS conditions arising from central nervous system dysfunction. Of these so-called primary disorders of somnolence, narcolepsy is the most well known and extensively studied, yet often misunderstood and misdiagnosed. Idiopathic hypersomnia, the recurrent hypersomnias, and EDS associated with nervous system disorders also must be well-understood to provide appropriate evaluation and management of the patient with EDS. This review summarizes the distinguishing features of these clinical syndromes of primary EDS. A brief overview of the pharmacological management of primary EDS is included. Finally, in view of the tremendous advances that have occurred in the past few years in our understanding of the pathophysiology of canine and human narcolepsy, we also highlight these discoveries.Introduction
Somnolence is a complex state, impacted by multiple determinants such as quantity and quality of prior sleep, circadian time, drugs, attention, motivation, environmental stimuli, and various medical, neurological, and psychiatric conditions. Clearly, somnolence is welcomed when sleep is desired, but it often becomes an unwanted symptom at other times. Pathological or inappropriate somnolence is clinically termed "excessive daytime sleepiness" (EDS), which is the focus of this review, specifically central nervous system (CNS) dysfunction yielding syndromes of EDS.Excerpt:
Hypocretin/Orexin System and Sleep Regulation
Hypocretins /orexins were only recently identified (in 1998, 1 year prior to the cloning of the canine narcolepsy gene). Two independent research groups made this discovery. One group called the peptides "hypocretin" because of their primary hypothalamic localization and similarities with the hormone secretin.[77] The other group called the molecules "orexin" after observing that central administration of these peptides increased appetite in rats.[78] Hypocretin-1 and -2 are produced exclusively by a well-defined group of neurons localized in the lateral hypothalamus. The neurons project to the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brain stem, particularly the locus coeruleus, (LC) raphe nucleus, and to cholinergic nuclei and cholinoceptive sites (such as pontine reticular formation), thought to be important for sleep regulation.[79]A series of studies have now shown that the hypocretin system is a major excitatory system that affects the activity of monoaminergic (dopamine, norepinephrine, serotonin, and histamine) and cholinergic systems with major effects on vigilance states.[80,81] It is thus likely that a deficiency in hypocretin neurotransmission induces an imbalance between these classical neurotransmitter systems, with primary effects on sleep-state organization and vigilance. Indeed, dopamine and/or norepinephrine contents have been reported to be high in several brain structures in narcoleptic Dobermans and in human narcolepsy postmortem brains.[82] These changes in humans are possibly due to the compensatory mechanisms, as drugs that enhance dopaminergic neurotransmission (such as amphetamine-like stimulants and modafinil [for EDS]) and norepinephrine neurotransmission (such as noradrenaline uptake blockers [for cataplexy]) are commonly used.[82] Histamine is another monoamine implicated in the control of vigilance, and the histaminergic system is also likely to indirectly mediate the wake-promoting effects of hypocretin.Interestingly, brain histamine contents both in hcrtr-2 gene-mutated and ligand-deficient narcoleptic dogs are dramatically reduced,[86] and the involvement of the histaminergic system in the pathophysiology of narcolepsy and therapeutic applications of histaminergic compounds[87] should be further studied.
Many measurable brain and body activities and compounds manifest rhythmic fluctuations over the 24-hour period. Whether hypocretin tone changes with zeitgeber time was assessed by measuring extracellular hypocretin-1 levels in the rat brain CSF across 24-hour periods, using in vivo dialysis.[88-90] The results demonstrate the involvement of a slow diurnal pattern of hypocretin neurotransmission regulation (as in the homeostatic and/or circadian regulation of sleep). Hypocretin levels increase during the active periods and are highest at the end of the active period, and the levels decline with the onset of sleep. Furthermore, sleep deprivation increases hypocretin levels.[88-90]
How hypocretin neuronal activity varies across different sleep stages is still unknown. Regardless of the firing pattern of the hypocretin neurons, our results suggest that basic hypocretin neurotransmission fluctuates across the 24-hour period and slowly builds up during the active period. Adrenergic LC neurons are typical wake-active neurons involved in vigilance control, and it has been recently demonstrated that basic firing activity of wake-active LC neurons also significantly fluctuates across various circadian times.[91] Several acute manipulations such as exercise and low glucose utilization in the brain, as well as forced wakefulness, increase hypocretin levels.[80,89,92] It is therefore hypothesized that a buildup /acute increase of hypocretin levels may counteract homeostatic sleep propensity, which typically increases during the daytime and during forced wakefulness.[89] Due to the lack of increase in hypocretin tone, narcoleptic subjects may not be able to stay awake for a prolonged period and do not respond to various alerting stimuli. Conversely, the reduction of the hypocretin tone at sleep onset may contribute to the profound deep sleep that normally inhibits REM sleep at sleep onset, and the lack of this system in narcolepsy may allow the occurrence of REM sleep at sleep onset.
Any thoughts???
poster:dove
thread:411549
URL: http://www.dr-bob.org/babble/20041103/msgs/411549.html