B R A I N S T O R M S Clinical Update

Awakening to the of Sleep and Arousal: Novel Neurotransmitters and Wake-Promoting Drugs © Copyright 2002 Physicians Postgraduate Press, Inc. Stephen M. Stahl, M.D., Ph.D.

Issue: Unique neurotransmitters acting at specific hypothalamic neurons promote either wakefulness or sleep. Drugs and diseases that modify neurotransmission at these sites can produce both desirable and undesirable changes in wakefulness.

One personal copy may be printed ew developments in the such activation: a newly characterized histamine output causes sedation or

psychopharmacology of projection from the hypothalamus and sleep (e.g., antihistamines that block H1 N sleep and wakefulness are the classical ascending reticular acti- receptors). Sleep-promoter neurons in leading to enhanced clinical insight vating system (ARAS) that arises from the ventrolateral preoptic area use the into disorders of sleep and arousal and the brainstem. neurotransmitters γ-aminobutyric acid to the development of novel treatments and galanin.1 for sleepiness and fatigue. A glimpse Getting Juiced into the neuroanatomical substrates and Numerous neurotransmitter “juices” Eyes Wide Open: chemical mediators of arousal is now arise from these various neurons and Stimulation Versus Wakefulness possible. mediate aspects of both sleep and The and psychophar- arousal. Particularly interesting are the macology of arousal suggest that 2 Getting Wired recently discovered peptides hypocretin types of arousal, each mediated by Recent advances in neuroanatomy 1 and 2 (named for their hypothalamic separate pathways and neurotransmit- are now providing a picture of how origin and homology to secretin), ters, may exist: stimulated vigilance and neuronal pathways mediate sleep and also called orexin A and B (because normal wakefulness.1Ð6 The former may wakefulness, allowing us to better un- they also stimulate appetite).3,4 Orexin/ involve external vigilance, with tense derstand how the ’s wires keep us hypocretin neurons are located in the hyperarousal, putting the individual on awake or “wired.” Several interesting lateral hypothalamus and are critical the lookout for threats from the environ- sites within the hypothalamus are at for maintaining normal wakefulness. In ment. Arousal of this type may be me- work here, including brain “pacemak- fact, when they malfunction or are de- diated by the monoamines dopamine, ers,” sleep promoters, and wake pro- stroyed, they cause narcolepsy with norepinephrine, serotonin, and acetyl- moters.1,2 The brain’s pacemaker is the daytime sleepiness and sleep attacks. choline via the ARAS. The ability to well-known suprachiasmatic nucleus These neurons apparently regulate activate the ARAS may enhance the that serves as an internal clock for regu- monoaminergic and cholinergic com- lating circadian rhythms, especially the ponents of the ARAS known to mediate BRAINSTORMS is a monthly section of sleep-wake cycle, in part by alternating important dimensions of arousal. They The Journal of Clinical aimed at the activation of either sleep-promoting may also regulate both sleep-promoter providing updates of novel concepts emerging from the that have relevance to the neurons (in the ventrolateral preoptic and wake-promoter neurons in the practicing . area) or wake-promoting neurons (in hypothalamus. Wake-promoter neu- From the Neuroscience Education Institute in Carlsbad, Calif., and the Department of Psychiatry the tuberomamillary nucleus and lat- rons in the tuberomamillary nucleus at the University of California San Diego. eral hypothalamus). Activation of cere- project to cortex and use the neuro- Reprint requests to: Stephen M. Stahl, M.D., 1 Ph.D., Editor, BRAINSTORMS, Neuroscience bral cortex is essential for achieving transmitter histamine. Thus, boosting Education Institute, 5857 Owens Street, Ste. 102, wakefulness. Two pathways provide histamine causes arousal and blocking Carlsbad, CA 92009.

468467 J Clin Psychiatry 63:6, June 2002 B R A I N S T O R M S Clinical Neuroscience Update

Take-Home Points ◆ The neuroanatomy of wakefulness appears to involve survival of an individual in activation of neuronal projections to cerebral cortex negative rebound effect of nonres- a hostile environment. The and is regulated by several key hypothalamic nuclei. torative sleep once it is turned off. other form© of Copyrightarousal may ◆ 2002The psychopharmacology Physicians of wakefulness Postgraduate is mediated Selective Press, activation Inc. of wake- be a more reflective type of by numerous neurotransmitters acting in hypothalamus fulness could lead to improve- calm wakefulness, in which and cortex, including the newly identified neurotrans- ment in the cognitive decrements there is internal vigilance mitters known as both orexins and hypocretins, the normally associated with sleep to executive functions as classical monoamine histamine, and several others. deprivation in anyone from a shift the individual focuses on ◆ A new wake-promoting drug, modafinil, activates the worker to a jet-lagged interna- cognitive tasks. Such wake- cerebral cortex by increasing neuronal activity in wake- tional traveler or fighter pilot fly- fulness may be mediated by promoting hypothalamic neurons and by decreasing ing halfway around the world.8 In neuronal activity in sleep-promoting hypothalamic the ascending histaminergic addition, activating internal vigi- neurons, which appears to be useful in treating neurons arising from the conditions associated with sleepiness and fatigue. lance systems may reduce the hypothalamus. The ability to sense of fatigue in patients with activate this system would One personal copy may be printed depression and physical illnesses lead to problem solving, learning, and the hypothalamus, perhaps due to an such as and might creativity. autoimmune process that destroys the even enhance cognitive symptoms in lateral portion of the hypothalamus.4,5 attention deficit disorder as well as Flip-Flopping the Sleep-Wake Switch Furthermore, drugs that compensate for cognitive and negative symptoms of Normal wakefulness may be some- such disruptions by acting on specific . thing akin to an all-or-nothing phenom- neurotransmitters within these various enon, with the hypothalamus providing neuroanatomical systems may have Summary a reciprocal switching circuit so that the therapeutic actions on disorders of Exciting new developments in the brain can either be “on” (calm wakeful- sleepiness and fatigue.5,7 Stimulants psychopharmacology of wakefulness ness) or “off” (asleep). Such an arrange- (e.g., amphetamine) and nonstimulants are clarifying the neurotransmitters, ment would limit intermediate states, (e.g., modafinil) can treat narcolepsy, pathways, and drugs that impact this allowing relatively brief times to be the former by activating both arousal important physiologic state. Selec- spent in transitions between the wake or systems, and the latter by selectively tively inducing normal wakefulness sleep states. One model of the normal activating normal wakefulness. without stimulating external vigilance sleep-wake cycle proposes that wake- may lead to therapeutic benefits not promoter and sleep-promoter neurons Psychopharmacologic Wakefulness only in sleep disorders but also in cog- inhibit each other, thus causing oscilla- on Demand nitive disorders and conditions associ- tion between wakefulness and sleep in a What is so interesting about the new ated with fatigue. ◆ rhythm determined by the brain’s inter- developments in this field is that it may nal clock (located within the supra- now be possible to activate the normal 1 chiasmatic nucleus). wakefulness pathway selectively and REFERENCES Disruption of wake- and sleep- on demand with novel wake-promoting 1. Saper CB et al. Trends Neurosci 2001;24: promoting pathways or their neuro- drugs. Theoretically, a person with the 726Ð731 transmitters would therefore result in wakefulness system “on” is experienc- 2. Salin-Pascual R et al. Neuropsychopharmacol- problems with wakefulness and arousal ing the cognitive chemistry of a nor- ogy 2001;25:S21ÐS27 1 3. Mignot E. Neuropsychopharmacology and could lead to fatigue and cognitive mal, well-rested state. By contrast, 2001;25:S5ÐS13 and executive deficiencies in problem so-called stimulants (e.g., amphet- 4. Ripley B et al. 2001;57:2253Ð2258 solving. Specifically, unstable on-off amine, caffeine) seem to nonselectively 5. Lin J-S et al. Proc Natl Acad Sci USA 1996;93: 14128Ð14133 switches could lead to insomnia or to activate both external and internal vigi- 6. Groopman J. Eyes Wide Open. New Yorker unwanted transitions into sleep during lance arousal systems. Theoretically, a 2001:52Ð57 wakefulness, e.g., narcolepsy. In fact, person with the external vigilance sys- 7. Scammell TE et al. J Neurosci 2000;20: 8620Ð8628 patients with narcolepsy have lost tem “on” may have motor hyperactiv- 8. Caldwell JA et al. Psychopharmacology 2000; their orexin/hypocretin signaling in ity, jitteriness, overconfidence, and a 150:272Ð282

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