CHAPTER 13: Sleep and Arousal

• Both sleep and arousal are active processes mediated by specific brain regions and neurotransmitter systems.

• Sleep can be divided into two phases, nonrapid eye movement (non-REM) and REM sleep, the latter being characterized by brain activity resembling that observed during the waking state.

• The different physiologic functions of sleep are unknown; a role in memory consolidation is likely.

• The initiation of non-REM sleep is controlled in part by GABAergic neurons in the preoptic/anterior hypothalamic area; the initiation of REM sleep is controlled by cholinergic cells in the pontine tegmentum.

• Sleep is controlled both by circadian rhythms and by the homeostatic drive produced by periods of wakefulness. Adenosine is an important mediator of the homeostatic drive for sleep.

• The suprachiasmatic nucleus is the primary pacemaker for the circadian regulation of sleep and other physiologic processes, in particular, for entraining circadian rhythms to environmental light.

• Circadian rhythms are produced, in part, by the complex transcriptional regulation of “clock” genes that have been conserved throughout evolution.

• Sleep disorders are a significant cause of morbidity. A major advance is the finding that decreased expression of the hypothalamic neuropeptide orexin (also called hypocretin) causes most human narcolepsy.

• Benzodiazepines and similarly acting drugs, which are positive allosteric modulators of GABA_A receptors, are the most common pharmacologic treatments for insomnia.

• General anesthetics, comprising diverse classes of compounds, induce a non-REM sleep-like state characterized by amnesia, analgesia, immobility, and hypnosis. Most general anesthetics act, at least in part, by facilitating inhibitory ion channels (including ligand-gated channels) or inhibiting excitatory ion channels.

Defining sleep and arousal is not a simple matter. Sleep is clearly different from hibernation, coma, or states produced by general anesthesia. The first part of this chapter presents a broad overview of the neurobiology of sleep and arousal states. The second part covers some of the major sleep disorders, the mechanisms of which are slowly being elucidated. The third part discusses the pharmacologic treatment of these disorders.

As with other behavioral states such as fear and reward (Chapters 15 and 16), sleep states, such as rapid eye movement (REM) and nonrapid eye movement (NREM) sleep, depend on specific neural circuits. However, certain phenomena that occur during sleep may also employ some of the circuitry that contributes to behavioral states during waking hours. Night terrors, for example, involve a partial arousal out of deep NREM sleep; patients exhibit powerful sympathetic activation including tachycardia, mydriasis, and diaphoresis, despite the fact that they remain asleep. In contrast, patients with REM behavior disorder may have bouts of violent behavior during REM sleep that are not accompanied by elevations in heart rate or blood pressure. Hence, states of sleep and arousal are complex and heterogeneous and cannot be explained by a simple rheostat model.

Before the beginning of the 20th century, sleep was conceptualized as a passive process; sleep and arousal were believed to reflect a continuous gradient of levels of consciousness. It was believed that the level of arousal corresponded to the number of neurons that were actively engaged in processing information, in much the same way that the illumination from a light bulb varies depending on the amount of electric current it receives. During the second half of the 20th century, however, it was discovered that distinct cell groups in the brainstem and forebrain are more active during sleep, demonstrating that the existing model was too simplistic.

An early clue that sleep is not merely a passive state but an active process emerged with the finding that particular brain regions must be intact for sleep to occur. It was discovered, for instance, that lesions of the anterior hypothalamus create a state of chronic insomnia, which suggested that activity in this region is necessary for sleep. In contrast, lesions involving the posterior hypothalamus create a state of hypersomnolence.

The advent of the electroencephalogram (EEG) in the 1930s permitted noninvasive assessment of brain function in humans and animal models. The EEG remains the central tool in studies of sleep and wakefulness. Accordingly, sleep states have been defined by EEG patterns. EEG uses scalp electrodes to detect electrical signals produced mainly by surface areas of the brain. The EEG has excellent temporal resolution, but because it integrates information coming from a very large number of neurons, it has very limited spatial resolution.

In 1948 it was discovered that stimulation of the reticular formation of the brainstem elicits EEG arousal that is independent of sensory afferent pathways. Thus, arousal began to be viewed as an intrinsic property of the brain mediated by specific cell groups rather than a simple correlate of increased sensory input. This change in perspective roughly coincided with the discovery that alertness and arousal have a circadian rhythmicity that is independent of the number of hours an individual sleeps. Studies of sleep-deprived individuals indicated that alertness increases in the midmorning from a nadir that occurs late at night despite a long period of continuous wakefulness. Such findings demonstrated that arousal is not a simple function of previous rest.

In the late 1950s, cats with pontine lesions were reported to have REM sleep without the normal loss of muscle tone (atonia) that occurs in this sleep stage (and presumably keeps humans and most probably other animals from acting out their dreams). In these studies the lesioned cats walked and exhibited attack and defense behaviors while they were unresponsive to external stimuli and their EEGs were in a REM state. Subsequent histochemical studies of the brainstem suggested that REM is a complex state that is controlled by several neurotransmitter systems; these studies laid the groundwork for electrophysiologic experiments in the 1970s that showed that the onset of REM is generated by cholinergic cells in the pontine tegmentum (PT) and that inputs from the noradrenergic locus ceruleus (LC) and serotonergic raphe nuclei (RN) inhibit REM (Chapter 6). These findings in turn led to the development of an influential reciprocal interaction model of REM regulation, which is described later in this chapter.

Normal sleep exhibits fairly stereotypic patterns as measured by the EEG 13–1. In adults, in the first hour of sleep, brain activity descends through a series of NREM stages into deep sleep. NREM stage 1 occurs during the transition between wakefulness and sleep and is defined by the presence of background theta activity (4–7 Hz) that comprises more than 50% of each 30-second epoch. NREM stage 2 is composed of a background rhythm of theta activity with superimposed burst–pause waveforms such as K-complexes (high-amplitude, slow-frequency electronegative waves followed by electropositive waves) and spindles (brief bursts of 7–14 Hz activity). NREM stages 3 and 4, together referred to as slow-wave sleep, are defined by the presence of slow-wave (0.1–4 Hz), or delta, sleep activity that comprises 20% and 50% of each epoch of sleep, respectively. The predominance of low-frequency activity in slow-wave sleep indicates greater synchrony in neuronal firing and leads to a summed polarization and depolarization large enough to be recorded by the EEG.

After approximately 90 minutes of NREM sleep, the brain’s electrical activity reascends through the same stages toward the first cycle of REM sleep. REM sleep is characterized by low-amplitude, mixed-frequency and desynchronized EEG activity that appears similar to the EEG of the normal waking state 13–1. The desynchronization of the EEG results from individual neurons being in many different states of activity. This EEG pattern is accompanied by REMs—hence the name REM sleep—and profound relaxation of limb muscles. The NREM–REM sleep cycle repeats itself four or five times in the course of the night, with decreasing amounts of slow-wave sleep and increasing amounts of REM sleep in successive cycles 13–2.

Intermittent awakenings are part of normal sleep and may serve an adaptive function; for example, they may enable changes in posture to minimize circulatory pooling or nerve compression, or appraisals of the environment to guard against possible threats. Humans are unaware of most of these brief awakenings because they experience retrograde amnesia for several minutes after resuming sleep. A common misperception is that dreams occur only during REM. In fact, dreams occur during all stages of sleep but tend to be more dramatic, varied, and vivid in the latter part of the night during REM.

Newborns spend 20 hours per day in sleep. These hours are characterized by an incomplete segregation between REM-like (or active) sleep and NREM-like (or quiet) sleep. By 6 months of age, REM and NREM sleep can be reliably distinguished. During the first 3 years of life, humans begin to segregate sleep and waking until they become two distinct, consolidated periods. During adolescence a precipitous drop in slow-wave sleep activity occurs. With advancing age there is a gradual decline in total hours of sleep together with an increase in the number of awakenings. The sixth and seventh decades of life are characterized by a decline in total slow-wave sleep activity, which correlates with a decline in EEG amplitude. Elderly people experience more awakenings, complain more often of insomnia, and shift more of their sleep time to the day in the form of naps. Older people have a propensity to fall asleep at earlier hours and to have more early morning awakenings (phase advance of circadian rhythms). The decline in total sleep time in healthy older subjects is relatively modest, however, with more severe declines often related to medical conditions, pain, or depression.

Each sleep stage is accompanied by specific physiologic changes. Slow-wave sleep is associated with a reduced metabolic rate and a decline in brain and body temperature. Electrophysiologic features of all four NREM stages of sleep include increased firing of sleep-active centers in the anterior hypothalamus, hyperpolarization of thalamocortical neurons, and burst–pause activity driven by the reticular thalamic nucleus. Broad systemic features of stages 1 to 4 include behavioral quiescence, low muscle activity, reduced blood pressure, reduced heart and respiration rates, reduced cortisol and thyroid hormone levels, and increased growth hormone, testosterone, prolactin, insulin, and glucose levels (Chapter 10).

REM sleep, in contrast, is a unique state of arousal characterized by brain electrical activity, cerebral blood flow, and brain glucose metabolism similar to that of wakefulness. REM sleep is accompanied by a generalized muscular atonia except for the extraocular muscles (thus the REMs) and the diaphragm. Clitoral or penile tumescence, phasic bursts of eye movements, and alternating acceleration and deceleration of heart and respiratory rates also characterize REM.

Electrophysiologic recordings during REM sleep have documented tonic cerebral activity, synchronized firing of hippocampal neurons in the theta frequency range, and phasic pontogeniculooccipital (PGO) spikes originating in the pons. Several limbic structures and regions of the hypothalamus and brainstem reach their highest firing rate during REM. Positron emission tomography (PET) studies in humans have shown that limbic structures such as the amygdala become metabolically active during REM sleep. Interestingly, despite the pattern of cerebral activation, the threshold for arousal from REM sleep is higher than that from NREM sleep.

The need to sleep is universal among mammals, birds, and reptiles and has been conserved in evolution. It has even been reported in Drosophila. Despite the obvious disadvantages of sleep, such as reduced vigilance against predators, it is necessary to sustain life. It is claimed that total sleep deprivation in rodents can result in death (although this result has been contested). Another striking observation that supports the importance of sleep has come from marine mammals, which must remain awake constantly in order to surface every few minutes for air. These mammals sleep unihemispherically; that is, one cerebral hemisphere exhibits sleep patterns detectable by EEG, while the other hemisphere remains awake. The persistence of sleep states in animals that must remain awake to breathe is a powerful indication that sleep serves an essential function.

Despite intense scientific research, no theory has convincingly explained the function of sleep. Questions regarding the amount of sleep that is needed, the stage of sleep that is most restorative, and the interventions that best promote healthy sleep remain unanswered. The popular belief that sleep is needed to restore the integrity of body functions makes some intuitive sense. Yet, this theory is accompanied by a false assumption that sleep is an inactive state. Because quiet wakefulness and sleep differ very little in terms of energy expenditure, it is unlikely that sleep and its attendant reduction in vigilance were conserved in evolution simply to save energy. Furthermore, no compelling evidence suggests that tissue rebuilding or an increase in protein synthesis is associated with sleep. Many types of external and internal stimuli, including ambient temperature, darkness, food intake, exercise, and endogenous immune factors, affect sleep, but none of these variables has provided clues to the core function of sleep.

Many hypotheses have been used to explain the functions of REM sleep, but these frequently focus on a particular feature of REM, such as PGO spikes, and ignore other features. One prominent and intriguing hypothesis is that REM is needed to enhance learning or to discard irrelevant memory traces. While sleep may be important for enhancing the consolidation of memories (see below), the evidence in support of a specific role for REM in this process remains incomplete. Another interesting hypothesis, which arises from observed relationships between the proportion of sleep spent in REM by species based on their degree of maturity at birth, is that REM is needed for early neurodevelopment in species, such as our own, characterized by marked immaturity at birth. However, this hypothesis does not adequately explain the persistence of REM in adulthood and the increased amount of REM sleep that occurs after sleep deprivation. Current hypotheses also fail to explain the functional significance of alternations between REM and NREM sleep cycles, although it appears that the length of these cycles in mammals correlates closely with brain size. Consequently, the function of sleep may relate to crucial molecular and cellular processes not yet adequately understood.

There is increasing evidence that sleep plays an important role in memory. Sleep in general seems to be important for memory processing: long-term memory consolidation and reconsolidation seem to occur during sleep. (These aspects of memory are discussed in greater detail in Chapter 14.) For example, during early nocturnal sleep when slow-wave sleep is predominant, hippocampus-dependent declarative memories are replayed, stabilized, and likely enhanced. On the other hand, late sleep, when REM sleep predominates, has been associated with amygdala-dependent emotional memory. There is also evidence suggesting a role for sleep in motor learning, specifically in post-training consolidation: a period of sleep after learning a motor task has been shown to improve performance. In such experiments, one group of subjects practices a task in the morning and is tested late in the day, while another group practices the task in the evening, is permitted to sleep, and then is tested after an equivalent time lapse as the “day-wake” group.

Several neural systems mediate the switching between wakefulness and sleep and between the different stages of sleep 13–3. These systems include the ascending reticular activating system (ARAS), the ventrolateral preoptic (VLPO) area, and the orexin/hypocretin system (Chapters 6 and 7).

The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.

The VLPO area of the anterior hypothalamus consists mainly of inhibitory neurons that release γ-aminobutyric acid (GABA) and the neuropeptide galanin. The VLPO neurons are likely to have reciprocal interactions with the ARAS and orexin neurons. The VLPO neurons inhibit and are inhibited by the TMN histamine neurons and REM-off monoamine neurons. Orexin neurons are located in the lateral hypothalamus. They are organized in a widely projecting manner, much like the monoamines (Chapter 6), and innervate all of the components of the ARAS. They excite the REM-off monoaminergic neurons during wakefulness and the PT cholinergic neurons during REM sleep. They are inhibited by the VLPO neurons during NREM sleep.

NREM Sleep

According to a simplified model, the onset of NREM sleep is driven by VLPO area neurons that exert an inhibitory effect on TMN histamine neurons 13–3. Consistent with this hypothesis is the finding that VLPO and TMN neurons exhibit opposite patterns of activity during the sleep–wake cycle. In contrast to the VLPO neurons, which are active during sleep, the TMN neurons are persistently active during wakefulness, reduce their firing during NREM sleep, and become inactive during REM sleep. The role of the TMN histamine neurons in sleep–wake activity explains how the older antihistamines such as diphenhydramine andchlorpheniramine, which are H₁ receptor antagonists (or inverse agonists), promote drowsiness and sleep. Newer antihistamines, such as loratadine, do not cross the blood–brain barrier and are without sedative effects. The older antihistamines are still marketed as over-the-counter sleep aids.

In the absence of tonic activity from the ARAS and TMN, which promotes wakefulness, higher-frequency oscillations in the cortex disappear, giving rise to the synchronous firing of a large thalamocortical neuronal ensemble. Thus, the delta wave and spindling rhythms observed during NREM sleep most likely reflect intrinsic properties of thalamic neurons, which synchronize the large thalamocortical network. Because a large number of neurons fire in synchrony at this stage, EEG recordings detect high-amplitude waves (see 13–1).

The brain structures involved in the control of NREM sleep are also crucial to thermoregulation. Some neurons in the preoptic area of the hypothalamus (POAH) are thermosensitive; they respond to changes in temperature by activating broad thermoregulatory mechanisms. In fact, as indicated previously, NREM sleep is associated with a lowering of the set point for body temperature, a loss of body heat, and a decline in energy metabolism. Warm-sensitive cells in the POAH area appear to be sleep-active, whereas cold-sensitive cells are active during wakefulness. Consistent with these observations, warm-sensitive POAH neurons increase their firing rates during the transition from wakefulness to NREM sleep, whereas cold-sensitive neurons reduce their firing rates during the onset of sleep. Furthermore, warming of the POAH induces NREM sleep, increases the length of NREM periods, and increases delta activity during slow-wave sleep. In contrast, POAH lesions result in chronic disruption of both NREM sleep and thermoregulation. It therefore appears that warm-sensitive neurons in the POAH regulate the onset and maintenance of slow-wave sleep. Interestingly, passive heating of the body improves sleep continuity in patients with insomnia.

REM Sleep

In contrast to the diffuse brain structures involved in NREM sleep, the neuroanatomy of REM-active structures is relatively circumscribed. As previously mentioned, the primary oscillator that drives REM sleep appears to be located in the PT 13–3. REM-on cholinergic neurons in the PT, which includes the pedunculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei, have high discharge rates during wakefulness and REM sleep and low discharge rates during NREM sleep. During NREM sleep, the VLPO area neurons start inhibiting the orexin neurons of the lateral and posterior hypothalamus. Consequently, the norepinephrine and serotonin REM-off cells, which are excited by orexin neurons during wakefulness, start to wane in activity, which gradually releases the cholinergic REM-on cells from this inhibitory effect. At the end of NREM sleep, the VLPO area neurons directly inhibit the REM-off cells, which completely disinhibits the REM-on cholinergic neurons and initiates REM sleep. Consistent with the inhibition of REM-on cells by serotonergic and noradrenergic inputs, antidepressant drugs, which increase the availability of synaptic serotonin or norepinephrine (Chapter 15), reduce REM sleep. Older tricyclic antidepressants, which are also anticholinergic (ie, they inhibit muscarinic cholinergic receptors), likely reduce REM sleep by the latter mechanism as well.

Via their heavy projections to thalamic nuclei and the reticular formation, the REM-on cells result in EEG desynchronization. Not surprisingly, application of cholinergic agonists or acetylcholinesterase inhibitors to the target cells in the thalamic nuclei or the reticular formation activates REM sleep, whereas muscarinic cholinergic antagonists suppress REM sleep.

Activity in the PT is responsible not only for initiating REM sleep but also for the physical manifestations of REM sleep. For example, cholinergic projections from the PT to the medulla and spinal cord induce muscle atonia, most likely by hyperpolarizing motor neurons and associated interneurons. REM-associated cortical asynchrony, phasic eye movements, and cardiopulmonary accelerations and decelerations involve projections from the pons to the hypothalamus and thalamus. Although discrete pontine structures initiate most tonic and phasic elements of REM sleep, other structures are involved in REM regulation. For example, orexin neurons appear to be critical for the regulation of REM sleep, as discussed in the section “Narcolepsy.” In addition, inputs from the amygdala and other limbic structures can influence phasic REM activity. This finding may explain why stress and depression are associated with increased phasic REM activity. Furthermore, lesions caudal and rostral to pontine REM-on cells profoundly alter the characteristics of REM sleep; for instance, such lesions can cause REM sleep without atonia, which can lead to the motoric expression of dreams. Such motor activity in humans during sleep has been associated with unintentional nocturnal violence against sleeping partners and injury from falls.

Sleep is partly controlled by a homeostatic drive that increases the propensity to fall asleep in response to the amount of prior wakefulness. A student who has “pulled an all-nighter” may take an afternoon nap in response to a strong homeostatic drive resulting from an unmet need for sleep. This homeostatic drive is reflected by the amount of EEG slow-wave activity. However, the propensity to sleep is also affected by a circadian process 13–4. The student who stays awake to study may feel increasingly tired throughout the night, and yet may feel more alert at 8:00 AM than at 4:00 AM, despite the fact that by 8:00 AM 4 additional hours of sleep debt have accumulated.

Homeostatic Control of Sleep

The homeostatic control of sleep is still poorly understood. A number of sleep-modulating substances have been identified, including adenosine, muramyl dipeptide, interleukin-1, delta sleep-inducing peptide, prostaglandin D₂, and tumor necrosis factor (TNF)-α. Extracellular adenosine decreases during slow-wave sleep and increases after prolonged wakefulness. During sleep deprivation, adenosine accumulates in the basal forebrain, especially in the substantia innominata extracellular spaces, and promotes sleep by inhibiting cholinergic neurons. Recovery sleep leads to a decline in adenosine levels. Adenosine may, therefore, serve to mark the duration of wakefulness as well as indicate an increased need for sleep. However, the evidence from adenosine receptor knockout mice suggests that adenosine has a modulatory rather than a direct sleep-generating effect. The alertness associated with the use of caffeine and related methylxanthines (theophylline, theobromine) is mediated primarily by their ability to block adenosine A₁ receptors, and to thereby block inhibition of the cholinergic arousal centers by adenosine (Chapter 8). The drugs also antagonize adenosine A_2A receptors, which are enriched in striatum; antagonism of the receptors is locomotor-activating, particularly in rodents, which contributes indirectly to arousal. Prostaglandin D₂, acting on prostaglandin D (PGD) receptors, has been shown to indirectly activate adenosine-dependent pathways in the basal forebrain, and thereby promote sleep indirectly. Interleukin-1 and TNF appear to modulate sleep in the context of acute inflammation or infection.

Circadian Control of Sleep

Circadian variations have been observed in virtually all organisms and physiologic processes. Such circadian cycles prepare an organism to feed, avoid predators, and cope with environmental fluctuations, such as changes in light and temperature. To be useful, circadian cycles must correspond to environmental events. Environmental variables that entrain the circadian pacemaker are called zeitgebers (time givers). Light is the primary zeitgeber that helps an organism adapt to the light–dark cycle as it varies across the seasons. Other zeitgebers that entrain the circadian clock are temperature, food availability, and social cues.

Mammalian circadian rhythms that are entrained by environmental light are controlled by the suprachiasmatic nucleus (SCN) 13–5, which is the primary pacemaker for neuroendocrine rhythms, the temperature cycle, and REM sleep periods. The SCN is located in the midline anterior hypothalamus immediately above the optic chiasm. Its importance is indicated by the loss of some important circadian rhythms and the disorganization of sleep–wake patterns that occur when the SCN is lesioned.

In mammals, a connection between retinal ganglion cells and the SCN (the retinohypothalamic pathway) allows the latter to receive direct input about ambient light that helps entrain circadian rhythms. Light-derived input to the SCN is conveyed also indirectly via the intergeniculate leaflet of the thalamus and the geniculohypothalamic tract. On exposure to light, retinal ganglion cells release melanopsin into the SCN, which in turn activates the sympathetic intermediolateral cell column in the thoracic spinal cord, which has a negative feedback loop with the pineal gland, resulting in inhibition of melatonin release 13–1. See Chapter 6 for the synthesis and structure of melatonin.

The SCN also receives serotonergic input from the RN and cholinergic inputs from the forebrain and brainstem. Moreover, it exerts control over circadian neuroendocrine and thermal rhythms through its projections to the paraventricular nucleus and to lateral and posterior areas of the hypothalamus. The SCN neurons influence the release of orexin, corticotropin-releasing factor, thyrotropin-releasing hormone, and gonadotropin-releasing hormone, and the activity of autonomic neurons (Chapters 9 and 10). Although SCN cells are predominantly GABAergic, the peptide neurotransmitters somatostatin, vasopressin, and vasoactive intestinal peptide (VIP) also may be released by SCN neurons to modulate the activities of certain sleep- and wake-promoting cells.

Molecular Control of Circadian Rhythms

In the last decade of the 20th century, several discoveries helped to elucidate the molecular basis of circadian timekeeping. The identification of the Clock gene in mammals, the Period and Timeless genes in Drosophila, and the Frequency gene in the fungus Neurospora illuminated conserved mechanisms for circadian regulation.

Each of the ~20,000 cells of SCN neurons expresses a molecular circadian clock. Intracellular circadian rhythms are maintained by the transcription of three Period genes (Per1–3), two Cryptochrome genes (Cry1, 2), the Clock gene, and the Bmal 1 gene 13–6. CLOCK and BMAL1 proteins form a heterodimer that is an active transcription factor (CLOCK:BMAL1). At the beginning of an organism’s wake time, the transcription and translation of Per and Cry genes are accelerated by CLOCK:BMAL1 heterodimers that have accumulated during the preceding sleep time. CRY and PER proteins start accumulating during the wake time, and their levels peak at the beginning of the organism’s subjective night. Complexes of CRY and PER proteins exert a negative feedback by inhibiting the CLOCK:BMAL1 heterodimers; hence, PER and CRY protein levels start to decline. Meanwhile, PER2 protein had activated the transcription of BMAL1. BMAL1 protein starts accumulating, and its level peaks during the night. New CLOCK:BMAL1 heterodimers are formed and start the cycle again the next day after they are released from the feedback inhibition of the CRY–PER complexes, the levels of which have been declining throughout the preceding night. These interlocking negative and positive feedback effects among the circadian gene products, which are subject to regulation by many other proteins (eg, several protein kinases including casein kinase 1), display an autonomous rhythm of approximately 24 hours. In addition to regulating one another, several circadian gene products regulate the expression of many other genes (eg, growth hormone) that in turn mediate circadian regulation of most physiologic functions in the body.

Molecular circadian mechanisms are sensitive to changes in light–dark cycles via the photoactivation of neuroreceptors in SCN neurons. As most airplane travelers have experienced, circadian rhythms can shift to conform to new light–dark cycles, although they do not always shift as efficiently as one might wish. How do circadian gene products, oscillating in their own time zone, adjust to a shift in the light–dark cycle? The exact mechanisms that underlie such adjustments are unknown. However, the administration of bright light at times other than those predicted by the regular light–dark cycle can result in altered patterns of gene expression in SCN cells. This finding indicates that external stimuli can affect the expression of specific genes, which in turn may influence the production or activity of circadian gene products.

While the SCN is considered the master circadian control region, and certainly the most important region for entraining circadian rhythms to environmental light, it is crucial to note that Clock and most other circadian genes are expressed ubiquitously in brain and peripheral tissues where they also exhibit circadian cycles. Indeed, in the absence of light, most of the body’s key circadian rhythms continue due to the intrinsic cycling of the molecular clock (CLOCK, BMAL1, CRY, PER, etc) that is typically just over 24 hours in diurnal animals. As well, many brain regions and peripheral tissues exhibit circadian rhythms that are partly independent of the SCN. It has been speculated, for example, that circadian rhythms endogenous to certain forebrain regions may contribute to circadian variations in mood, reward, and other complex functions. Finally, several genes homologous to Clock, such as NPAS (neuronal pas domain–containing transcription factor), can mediate molecular circadian rhythms in the absence of CLOCK protein itself. This information underscores the complexity of the molecular and neural circuit basis of circadian rhythms in physiology and behavior.

Difficulties related to sleep affect virtually all individuals at some point during their lives. Up to 10% of the general population has recurrent sleep difficulties. Sleep disturbances can be categorized as primary or secondary sleep disorders, the latter resulting from primary neuropsychiatric or general medical conditions. Examples of primary sleep disorders are given in 13–1.

Dyssomnias

Dyssomnias include primary insomnia, primary hypersomnia, narcolepsy, breathing-related sleep disorders, circadian rhythm sleep disorder, and other conditions. Most of these disorders are syndromes that are defined only by clinical signs and symptoms. Many are heterogeneous, and the molecular and cellular underpinnings remain poorly understood.

Primary insomnia

This disorder, which is characterized by difficulty in initiating and maintaining sleep, causes significant psychological distress and impairment at school or work. Primary insomnia can be characterized objectively with polysomnography, which demonstrates an increased number of awakenings 13–7. Although the biology of insomnia is not well understood, it is increasingly viewed as a disorder of hyperarousal. Subjects with primary insomnia have an elevated 24-hour metabolic rate and a decreased propensity to sleep when given the opportunity to nap during sleep latency tests. Nonpharmacologic interventions that reduce arousal, including biofeedback, meditation, and relaxation therapy, are effective in the treatment of primary insomnia. Sleep hygiene also promotes healthy sleep through nonpharmacologic, common-sense measures; these include adherence to a stable sleep–wake schedule, a reduction in the use of caffeine and other stimulants, a reduction in the use of alcohol, reduction of alerting stimuli in the sleep environment, plus regular exercise. Behavior modification therapy helps reduce the conditioned association between the sleep environment and wakeful arousal. Sleep restriction therapy and stimulus control behavior modification reduce the amount of awake time spent in bed. Patients who undergo sleep restriction therapy are instructed to get out of bed after a given period of wakefulness (approximately 15 minutes), and are advised not to return to bed until they feel tired enough to sleep. In this way, the association between being in bed and going to sleep is strengthened, and the association between being in bed and “tossing and turning” is weakened.

Primary hypersomnia

Patients who experience excessive somnolence are diagnosed with primary hypersomnia when other disorders of somnolence, such as narcolepsy and sleep apnea, have been ruled out. Subjects with this disorder appear to sleep longer during the day and have a greater propensity to fall asleep compared with normal controls. Primary hypersomnia is not well understood biologically but is believed to involve a disturbance of pathways that mediate wakeful arousal. Treatment primarily involves the use of psychostimulants, as discussed later in this chapter.

Narcolepsy

Narcolepsy affects 0.02% of the population worldwide and is characterized by excessive daytime sleepiness, cataplexy (a sudden loss of muscle tone often associated with strong positive emotion), sleep paralysis, and hypnagogic hallucinations (hallucinations that occur with the onset or termination of sleep). Narcolepsy in humans is caused by the loss of orexin (hypocretin)-producing neurons (Chapters 6 and 7). Such neurons, located in the lateral and posterior hypothalamus 6–25, 13–3, excite monoaminergic neurons during wakefulness and cholinergic neurons during REM sleep. Histamine neurons in the TMN of the hypothalamus, which play a critical role in arousal, express orexin receptors at high levels. In addition, orexin neurons have reciprocal connections to the noradrenergic LC and the serotonergic dorsal raphe (Chapter 6).

Initial clues to the pathophysiology of narcolepsy came from dog and mouse models. The dog model of narcolepsy, like the human disorder, is characterized by sleepiness and cataplexy (induced in the dog, eg, by the positive stimulus of food). Canine narcolepsy, unlike the human disorder, is transmitted as an autosomal recessive genetic disorder, caused by loss-of-function mutations in the orexin OX₂ receptor gene. In the mouse, experimental disruption of the gene encoding orexin peptides produced a narcolepsy-like disorder and feeding abnormalities. In humans, some cases of narcolepsy cluster in families, but most cases appear sporadic.

Human narcolepsy typically begins during adolescence. Unlike the animal models, human narcolepsy is only very rarely associated with mutations in the genes encoding orexin peptides or receptors. Most human cases appear to be associated with a significant decrease in levels of orexin A in cerebrospinal fluid, which is now a diagnostic test for the disorder. In cases studied postmortem, there is a selective loss of orexin neurons in the hypothalamus, with nearby nonorexin neurons being preserved 13–8. Narcolepsy is strongly associated with certain HLA antigens, and onset often follows infections. This picture is consistent with autoimmune destruction (Chapter 12) of orexin neurons, in analogy with autoimmune destruction of beta islet cells of the pancreas in type 1 diabetes. In China there was a spike in diagnosis of narcolepsy following the H1N1 influenza pandemic in 2009. In Finland a particular vaccine for the 2009 H1N1 influenza strain was associated with increased incidence of narcolepsy.

It has been hypothesized that loss of orexin neurons leads to decreased excitation of the monoaminergic neurons during wakefulness and consequently a tendency for the cholinergic neurons to escape from monoaminergic inhibition, resulting in sudden attacks of catalepsy and REM intrusions. This hypothesis is supported by the observation that administration of cholinomimetic agents exacerbates cataplexy in narcoleptic dogs, while administration of anticholinergic agents decreases cataplexy. Antidepressant drugs that block the reuptake of norepinephrine, and therefore enhance noradrenergic transmission at synapses with REM-off neurons, are effective anticataleptic agents. Orexin receptor agonists would be potentially important treatments, but the development of peptide agonists is challenging (Chapter 7). Moreover, an orexin agonist would require a short half-life or it would interfere with needed periods of sleep.

Lacking orexin agonists, treatment of hypersomnolence is based on administration of psychostimulants (such as amphetamine) or modafinil. Reduction of cataplexy is based on REM-suppressing drugs, such as tricyclic antidepressants (eg, imipramine) and SNRI antidepressants (eg, venlafaxine).

Sleep apnea

Sleep apnea, a breathing-related sleep disorder, is a common, age-related condition characterized by oropharyngeal collapse during sleep. Such collapse causes sleep fragmentation, hypoxia, pulmonary and systemic hypertension, and cardiac arrhythmias. Obstructive sleep apnea can be caused by obesity or anatomic factors, such as micrognathia, that predispose patients to airway occlusion during sleep. Central sleep apnea is secondary to impaired central respiratory drive; it is associated with congestive heart failure and advanced age, and occurs in 30% of men older than 60 years of age. Treatment may involve behavior modification, including weight loss and sleep position therapy; the use of mechanical devices to eliminate airway collapse, such as continuous positive airway pressure (CPAP); the use of dental appliances that adjust the position of the jaw and tongue; or surgery to enhance the size of the oropharynx.

Circadian rhythm sleep disorders

Some of these disorders, which are caused by a misalignment between behavioral waking activity and the endogenous circadian cycle, are perhaps not properly classified as primary sleep disorders. They are chronobiologic disorders caused artificially by jet travel across multiple time zones, or by shift work that results in a rapidly changing sleep–wake cycle. Clinical manifestations of these disorders, which include sleepiness, insomnia, diminished attention, gastrointestinal discomfort, and fatigue, vary depending on the juxtaposition of the underlying circadian cycle and sleep–wake behavior.

Advanced sleep phase syndrome (ASPS) is a rare autosomal dominant disorder that results in abnormal circadian behavior. Individuals sleep and wake earlier than desired (from about 1900 hours in the evening to 0400 hours in the morning). The first described gene mutation for familial ASPS was a missense mutation in the Per2 gene (serine-to-glycine). Recently, another single missense mutation in the casein kinase 1 delta (CK1δ) gene (threonine-to-alanine) was found to be associated with familial ASPS humans. CK1δ binds and phosphorylates mammalian PER proteins, thereby regulating their stability, subcellular localization, and the timing of the molecular clock. However, most cases of familial ASPS are not caused by this mutation.

Delayed sleep phase syndrome (DSPS) is the most frequent sleep disorder among young adults. It is characterized by persistently delayed sleep–wake timing (sleep from 0400 hours in the morning to noon). It is highly comorbid with attention deficit hyperactivity disorder (ADHD) (Chapter 14). DSPS has been associated weakly with several circadian-related genes, including Per3 and the arylalkylamine N-acetyltransferase gene, the rate-limiting enzyme in the synthesis of melatonin. However, the genesis of DSPS is likely complex in most individuals for whom the genetic and other causative factors remain largely unknown.

Parasomnias

Parasomnias are represented by nightmares, sleep or night terrors, sleepwalking, and other conditions that arise during stage 4 sleep. They are considered disorders only when their frequency, severity, or persistence disrupts the normal functioning of an individual. Excessive and severe nightmares are strongly associated with psychological trauma and often are seen in the context of posttraumatic stress disorder (Chapter 15). Night terrors and sleepwalking occur predominantly in children and involve a partial awakening out of slow-wave sleep. Children affected by night terrors experience extreme fear and sympathetic activation without fully awakening; consequently, they are difficult to console, much to the consternation of alarmed parents. In most cases, night terrors represent a benign condition that a child is likely to outgrow. Sleepwalking similarly involves partial arousal from deep slow-wave sleep. Although this disorder typically is innocuous, the persistence of sleepwalking in adults can be associated with psychopathology, including schizophrenia and mood disorders. Medications that are effective in the treatment of these parasomnias have yet to be developed.

Benzodiazepines

Benzodiazepines became available in the late 1950s and rapidly replaced the barbiturates as preferred sedative–hypnotics. Their wide acceptance resulted from their greater safety, including lower risks associated with overdose and abuse compared with those of the barbiturates and related sedative–hypnotics such as methaqualone, ethchlorvynol, meprobamate, and chloral hydrate; benzodiazepines also are less likely to induce hepatic metabolism of other drugs. Yet, like barbiturates and related sedative–hypnotics, benzodiazepines and related drugs bind to and facilitate the functioning of GABA_A receptors. Their mechanisms of action and general pharmacology are discussed in greater detail in Chapters 5 and 15. The chemical structures of representative benzodiazepines used as sedative–hypnotics are shown in 13–9.

Benzodiazepines promote the onset of sleep and sleep continuity in the treatment of insomnia. They also are commonly used as anxiolytics (Chapter 15). Much of the clinical art of benzodiazepines and other treatments for insomnia involves an understanding of the importance of drug half-life in determining appropriate drug therapy and minimizing adverse effects 13–2. Long-acting benzodiazepines, such as flurazepam and chlordiazepoxide, have active metabolites with half-lives in excess of 200 hours; their use often interferes with daytime alertness and is associated with more errors while driving an automobile compared with the use of shorter-acting agents. In contrast, benzodiazepines with extremely short half-lives (2–4 hours), such as triazolam, are useful for promoting the onset of sleep, but may be of less benefit to those who have difficulty maintaining sleep. Such short half-life agents can cause rebound insomnia during the latter half of the night, which can be viewed as a mild withdrawal syndrome that occurs in response to a single dose of the benzodiazepine. Repeated use of these agents can lead to more significant rebound insomnia and anxiety; however, the slow tapering of these agents can minimize the occurrence of a discontinuation syndrome. For these reasons, compounds with intermediate half-lives (eg, temazepam) are optimal for most individuals. Benzodiazepines are also associated with anterograde amnesia, especially if used in high doses or taken with alcohol. The drugs suppress the total amount of REM sleep and alter the time spent in stages 1 to 4; consequently, sleep produced by a sedative–hypnotic may not be as physiologically useful as normal sleep. Also, tolerance can develop to the sleep-promoting effects of benzodiazepines with daily use. Although zaleplon, zolpidem, and eszopiclone are not chemically classified as benzodiazepines 13–9, they act on the benzodiazepine site of the GABA_A receptor with virtually equivalent results. They have the same benefits and liabilities of short-to-intermediate half-life benzodiazepines.

Attempts to improve the long-term treatment of insomnia have addressed the various liabilities of drugs that act at the benzodiazepine site of the GABA_A receptor. One strategy, which remains speculative, might involve the use of partial agonists at this site; such drugs might be designed to cause sedation without producing tolerance. Another strategy might be to take advantage of the molecular diversity of GABA_A receptor subunits. Because the sedative effects of benzodiazepines appear to be mediated predominantly by one particular GABA_A receptor α subunit, the α₁ subunit (Chapters 5 and 15), drugs might be developed that are selective for this subunit and therefore unlikely to cause the deleterious cognitive effects of previously mentioned agents. Certain currently available drugs (eg, zolpidem and eszopiclone) show some preference for this subunit, but true subunit-selective benzodiazepine-like drugs are not yet available.

Nonbenzodiazepine Sedative–Hypnotic Agents

Several nonbenzodiazepine classes of drugs are currently used to promote sleep. Antihistamines, specifically the first-generation H₁ receptor inverse agonists—commonly referred to as antagonists—are frequently used and in fact are the active ingredients in most over-the-counter sleep remedies. They are able to penetrate the blood–brain barrier because of their lipophilicity, relatively low molecular weight, and lack of recognition by the P-glycoprotein efflux pump (Chapter 2). Examples of these medications include diphenhydramine 13–9, dimenhydrinate, chlorpheniramine, hydroxyzine, and promethazine. However, these drugs are less effective than benzodiazepines and are associated with more adverse daytime effects. Antihistamines also can adversely affect memory and psychomotor performance, even after the drugs are no longer detectable in the general circulation. Many people report the sensation of being “in a fog” for as many as 24 hours after taking an antihistamine.

As H₁ inverse agonists, antihistamines combine with and stabilize the inactive form of the H₁ receptor, shifting the equilibrium toward the inactive state. However, because the histaminergic neurons of the TMN of the hypothalamus are quiescent during sleep, antihistamines may cause more sedation during waking hours than promotion of sleep during the sleep cycle. Several tricyclic antidepressants and antipsychotic drugs block H₁ receptors, which contributes to the sedative effects of these agents. Another strategy for promoting sleep may involve the use of an H₃ receptor agonist. As described in Chapter 6, H₃ receptors are inhibitory autoreceptors on histaminergic neurons of the TMN. An agonist at these receptors, for example, R -α-methylhistamine, would be expected to reduce the activity of the neurons and thereby promote sleep. This approach has not yet been tested in humans.

Sodium oxybate (γ-hydroxybutyrate [GHB]) is a naturally occurring central nervous system (CNS) metabolite. It is found in highest concentration in the hypothalamus and basal ganglia. GHB is given to consolidate sleep, increase total nocturnal sleep time, and decrease sleep paralysis, hypnagogic hallucinations, and nightmares. Patients report progressive restfulness on awakening. Patients with narcolepsy report a decrease in cataplexy frequency. GHB is often referred to as a date rape drug, used to induce sleep in unsuspecting victims. The mechanism of action of GHB is poorly understood. It may be an agonist at GABA_B receptors; it also may be metabolized into GABA and thereby activate other GABA receptors. Another date rape drug, flunitrazepam (also known as Rohypnol or roofies), is a benzodiazepine agonist with a long half-life.

Trazodone is marketed as an antidepressant but is less effective in the treatment of depression than many other available agents. However, trazodone is sedating and is sometimes used to promote sleep. It improves sleep continuity and also subjective sleep quality. Although it is frequently recommended because of a putative lack of associated tolerance, data regarding its long-term efficacy have not been obtained. Trazodone is an agonist at several 5HT receptors; however, its mechanism of action in promoting sleep remains undetermined. Mirtazapine is another antidepressant known clinically for its sedative effect, which is thought to be related to the blockade of serotonin 5HT₂ receptors.

The melatonin system has been examined as a potential target for new sedative–hypnotic agents. Endogenous melatonin is synthesized exclusively in the pineal gland from tryptophan and serotonin (Chapter 6). Its physiologic role in the control of circadian rhythms and sleep remains uncertain. Exogenous melatonin has been shown to help reset the circadian clock in some experimental situations 13–1. It is commonly used to treat jet lag in individuals who travel across multiple time zones. Moreover, it has been used to help shift workers better adjust to new work hours, although its efficacy when used for these purposes has not been established in well-designed clinical trials. Its efficacy in the treatment of noncircadian insomnia also has not been supported by convincing evidence. Moreover, the safety of over-the-counter melatonin preparations in the United States has yet to be determined; indeed, even the composition of most of these preparations remains unknown because of the lack of regulatory oversight by the US Food and Drug Administration (FDA). The dose commonly available in health food stores has been determined to produce a level of melatonin that is 10 times greater than peak physiologic levels. Elevated concentrations of melatonin have been associated with endocrine disturbances such as amenorrhea in females and hypogonadism in males. Melatonin also can lead to the asynchrony of circadian physiology if used frequently at different times of the day. Melatonin produces its effects in mammals via activation of two G_i/o-linked receptors, termed MT₁ and MT₂, and knockout mice are now being used to determine their selective physiologic functions. The pharmaceutical industry currently is attempting to develop agonists that are selective for these melatonin receptors, such as the recently marketed ramelteon. However, studies of the efficacy of these agents to date have been disappointing.

There is considerable enthusiasm toward the recent development of orexin receptor antagonists for the treatment of insomnia. Several clinical trials have demonstrated that so-called dual orexin receptor antagonists, which block OX₁ and OX₂ receptors, as well as selective OX₂ antagonists, are highly effective at inducing and maintaining sleep. Suvorexant 13–9 is an example of a dual antagonist; it was approved by the FDA in August 2014 for treatment of insomnia. An interesting theoretical difference between orexin antagonists versus GABA_A-acting sedative–hypnotics is that the former suppress mechanisms of natural arousal while the latter suppress CNS activity globally. Given that most cases of insomnia involve hyperarousal and not a failure of CNS inhibition, it is possible that orexin antagonists may prove more effective in treating insomnia with fewer side effects. However, such speculation must be viewed with caution until extensive clinical experience with orexin-based agents becomes available.

Drugs That Increase Alertness

The drugs used most commonly to promote wakefulness are caffeine—for example, in coffee, soda, and over-the-counter stimulants—and related substances such as theophylline in tea and theobromine in chocolate. Although these drugs have several mechanisms of action, their stimulant properties are most closely associated with antagonism of adenosine receptors, particularly that of A₁ and possibly A_2A receptors as stated earlier (Chapter 8). The medicinal use of these drugs is limited by side effects such as nausea, headache, and tremulousness, which are common at clinically relevant doses. More selective antagonists of adenosine receptors, which have yet to be developed, may offer the clinical benefits of these agents without such unpleasant side effects.

The most potent agents that promote wakefulness are amphetamine-like psychostimulants, including D-amphetamine, methamphetamine, methylphenidate, mazindol, and pemoline. These drugs increase the synaptic levels of dopamine, serotonin, and norepinephrine primarily by blocking their reuptake or promoting their release (Chapters 6, 15, and 16). Actions on the dopamine system are believed to be most important for the stimulant effects of these drugs. Amphetamines remain the treatment of choice for narcolepsy. Although these drugs offer important symptomatic improvement in many patients, their use is associated with complications such as nighttime insomnia, tolerance, dependence, and in some cases addiction.

Modafinil, a (diphenyl-methyl)-sulfinyl-2-acetamide derivative, is another wakefulness-promoting drug approved by the FDA. It increases alertness and vigilance in normal individuals and in patients with narcolepsy, although it is clearly less efficacious than amphetamines. However, modafinil shows fewer cardiovascular side effects and less abuse potential compared with amphetamines. Of note, modafinil reduces subjective sleepiness and improves wakefulness, but—unlike amphetamine—does not reduce cataplexy. The mechanism of action of modafinil is not yet established with certainty. The drug inhibits the dopamine transporter, to which it binds with micromolar affinity, and its stimulant actions are lost in mice lacking this transporter. However, modafinil’s pharmacologic effects in humans are sufficiently distinct from those of amphetamine and other psychostimulants to raise questions about its underlying mechanisms. One possibility is that modafinil exerts a distinct effect on the dopamine transporter protein compared with the psychostimulants, resulting in different functional consequences. It is also possible that modafinil has additional direct actions on other neurotransmitter systems, although this remains speculative.

Several antidepressants alter the sleep–wake cycle. Some of these drugs exhibit strong antagonism of H₁ histamine and muscarinic cholinergic receptors, which mediates the ability of these drugs to promote sleep independently of their antidepressant actions. However, several antidepressants such as fluoxetine and bupropion, which have an amphetamine-like structure (Chapter 15), exert the opposite effect in some patients and can lead to insomnia. Why some serotonin-acting antidepressants, such as trazodone, promote sleep while others, for example, fluoxetine, disrupt sleep in a subset of patients remains unknown but may be related to the different groups of 5HT receptors that are activated by these medications.

H₃ antagonists or inverse agonists have been considered as wake-promoting and procognitive agents. These drugs, by opposing the activity of inhibitory H₃ autoreceptors on histaminergic neurons, would be expected to promote histamine release throughout the CNS. However, clinical trials that have examined the ability of H₃ antagonists/inverse agonists to promote wakefulness have generally been disappointing.

Many distinct but interdependent neural pathways regulate the sleep–wake cycle. Because each of these pathways is subserved by distinct neurotransmitters, many pharmacologic agents can influence sleep patterns. The cellular and molecular mechanisms involved in the regulation of sleep and circadian rhythms require more investigation, but it is anticipated that the elucidation of these mechanisms will lead to new targets for the effective pharmacologic treatment of sleep disorders.

General Anesthetics

Despite nearly two centuries of widespread use, the mechanisms through which drugs produce a state of anesthesia remain poorly understood. Initial hypotheses revolved around the discovery that an anesthetic drug’s potency correlated with its solubility in olive oil. This finding, coupled with the low potency of most general anesthetics (micromolar to millimolar), slowed identification of specific molecular targets and led to the lipid theory of anesthetic action, in which anesthetic effects were thought to be mediated by nonspecific interactions within lipid membranes. This lipid theory of anesthetic action dominated thinking for more than 80 years until the 1980s when anesthetics were shown to interact directly with the firefly luciferase protein in a lipid free preparation. Rapidly thereafter, researchers focused on ion channels as potential molecular targets of general anesthetic agents.

At clinically relevant concentrations, general anesthetics (including all volatile ether-based anesthetics—isoflurane, sevoflurane, desflurane, and enflurane—as well as the halogenated volatile alkane anesthetic, halothane) act as positive or negative allosteric modulators of many ligand-gated ion channels, for example, GABA_A, NMDA and AMPA glutamate, nicotinic acetylcholine, and glycine receptors (Chapters 5 and 6). The anesthetics also regulate several types of ion channels, such as two-pore K⁺ channels, voltage-gated Na⁺ channels, and the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels (Chapter 2). The net effect of anesthetics is to hyperpolarize resting membrane potentials (mainly by activating two-pore K⁺ channels) and to enhance synaptic inhibition and inhibit excitation. For example, at GABA_A receptors, most volatile and intravenous anesthetics (eg, propofol and etomidate) prolong the channel open time by enhancing the gating of the receptor by GABA. At glutamatergic synapses, volatile anesthetics act presynaptically to decrease glutamate release. Other nonhalogenated inhaled anesthetics (xenon, nitrous oxide, and cyclopropane) and the intravenous dissociative anesthetic ketamine (Chapters 15 and 16) depress glutamatergic transmission postsynaptically by blocking NMDA glutamate receptors; some also activate two-pore K⁺ channels.

While the molecular targets of anesthetic action have been the focus of intense investigation over the past two decades, the critical neuroanatomic substrates on which anesthetic drugs act have received relatively less attention. General anesthesia is a state defined by a collection of specific behavioral end points including amnesia, analgesia, immobility, and unconsciousness. We focus here on anesthetic-induced unconsciousness as an example of how the behavioral features of general anesthesia are being understood neurobiologically, although parallel efforts are under way to understand other features of anesthesia.

The hypnotic component of general anesthesia (defined experimentally as a lack of perceptive awareness of nonnoxious stimuli) shares many similarities to that of NREM sleep 13–3. However, one crucial difference is that even the deepest sleeper can be awakened by external stimuli, while the anesthetized individual will not reawaken until the anesthetic drugs are discontinued. Nonetheless, similarities led to the hypothesis that anesthetic drugs may exert their hypnotic effects via specific actions on NREM sleep–promoting circuits. When given in hypnotic doses, anesthetic drugs cause a breakdown in cortical–cortical communication as occurs in NREM sleep. Additionally, although sensory information continues to flow forward along lateral-parietal and mesial-temporal pathways, selective disruption of cortical feedback is a newly recognized feature of anesthetic-induced unconsciousness. This disruption of cortical feedback occurs with anesthetics as diverse as sevoflurane, propofol, and ketamine. However, controversy remains as to whether anesthetic-induced unconsciousness occurs directly as a result of a top-down cortical failure or whether impairing subcortical sleep–wake, bottom-up systems is the initiating event, which subsequently alters cortical function to cause loss of consciousness.

Anesthetics clearly alter function at multiple sites of the ARAS, where they may quench conscious wakefulness in part by disrupting signaling from the noradrenergic neurons of the LC, the histaminergic neurons of the TMN, and the orexinergic neurons of the lateral and posterior hypothalamus. Moreover, systemic delivery of anesthetics as structurally distinct as propofol, barbiturates (eg, pentobarbital), dexmedetomidine (an α₂-adrenergic agonist), and the volatile anesthetics (eg, isoflurane and sevoflurane) activates endogenous sleep-promoting neurons of the VLPO. Nevertheless, we also know that not every anesthetic uses these same ARAS systems en route to unconsciousness as highlighted by ketamine.

Unraveling the mysteries of how anesthetic drugs reliably and reproducibly cause a loss of consciousness, along with their other many effects, remains an area of active investigation.