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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Int Anesthesiol Clin. Author manuscript; available in PMC 2009 September 16.
Published in final edited form as:
PMCID: PMC2745232
NIHMSID: NIHMS131213

Neurochemical Modulators of Sleep and Anesthetic States

The regulation of consciousness is a fundamental question that has a long and storied association with philosophy. Today, consciousness studies command a central position in contemporary neuroscience1-3. The complexities of consciousness studies and the pressing demands of clinical care have led most anesthesiologists to focus on research problems with pragmatic outcomes. Yet the ability to accurately assess and manipulate states of consciousness with anesthetic drugs is the ultimate concern for every surgical patient and anesthesia provider. This volume recognizes consciousness studies as a legitimate and accessible concern for anesthesiology. This chapter considers the relationship between molecules known to regulate the loss of consciousness during anesthesia and molecules that regulate the loss of consciousness during physiological sleep. Sleep neurobiology has been shown to provide unique insights into the study of consciousness4-6. The proposal7,8 that neuronal networks that evolved to generate states of sleep and wakefulness also contribute to the generation of anesthetic states has been supported by many laboratories9-19. There is evidence that the loss of consciousness during sleep is caused, in part, by the loss of functional connectivity and information processing20. Functional connectivity is critically dependent on neurochemical transmission. Therefore, this chapter focuses on intravenous and volatile anesthetics that have been shown to alter endogenous neurotransmitters known to regulate states of consciousness. Reviews on sleep from an anesthesiology perspective are available elsewhere8,21-24.

The present overview is derived from a September 2007 PubMed title search of peer-reviewed papers linking 10 commonly used anesthetics with 11 endogenous molecules known to regulate states of consciousness. The list of intravenous anesthetics includes propofol, pentobarbital, ketamine, etomidate, and midazolam. The list of volatile anesthetics includes isoflurane, sevoflurane, nitrous oxide, xenon, and desflurane. The 11 endogenous molecules known to regulate sleep/wake states25 include acetylcholine (ACh), gamma-aminobutyric acid (GABA), glutamate, adenosine, dopamine, histamine, serotonin, norepinephrine, hypocretin/orexin, glycine, and galanin. This 10 by 11 matrix was searched from 1950 to 2007 and identified 660 references. A search of the last 10 years (1997 to 2007) revealed a total of 192 references (Tables 1 and and22).

Table 1
Intravenous Anesthetic Agents and Sleep-Related Neurotransmitters
Table 2
Volatile Anesthetic Agents and Sleep-Related Neurotransmitters

I. Intravenous Anesthetics Alter Neurotransmitters that Regulate Sleep and Wakefulness

The endogenous neurotransmitters and neuromodulators ACh, GABA, glutamate, the monoamines (dopamine, histamine, serotonin, and norepinephrine), and adenosine contribute to generating and maintaining states of sleep and wakefulness. The following section selectively highlights studies investigating the effects of the most cited agents (Table 1), propofol and ketamine, on these neurotransmitter systems.

1. Propofol

Propofol was successfully introduced into clinical practice during the late 1980s. Propofol is a small hydrophobic alkylphenol derivative and its anesthetic actions are mediated primarily via the GABAA receptor26. Propofol also alters the actions of other sleep-related neuromodulators. As reviewed below, the anesthetic effects of propofol also may be mediated by its effects on monoaminergic, GABAergic, glutamatergic, cholinergic, and adenosinergic neurotransmission in brain regions known to regulate sleep and wakefulness.

1.1 Monoamines

A consistent finding from studies of sleep neurobiology is that monoamines promote wakefulness (reviewed in25). Serotonin containing neurons in the dorsal raphe, norepinephrine containing neurons in the locus coeruleus, and histaminergic neurons in the tuberomammillary nucleus discharge at their fastest rates during wakefulness, slow their discharge rates during non-rapid eye movement (NREM) sleep, and are silent during rapid eye movement (REM) sleep. This wake-on/sleep-off discharge pattern is consistent with a role for these monoaminergic neurotransmitters in promoting wakefulness. Interestingly, although dopaminergic neurons in the ventral tegmental area do not change their discharge rates across the sleep-wake cycle, a large body of evidence demonstrates that dopamine also promotes wakefulness (reviewed in12).

The cell groups described above provide monoaminergic input to the prefrontal cortex, which contributes to the regulation of behavioral arousal27. Serotonin levels in rat frontal cortex decrease during sleep compared to wakefulness28, as would be predicted by the wake-on/sleep-off discharge pattern of serotonergic neurons. Similarly, norepinephrine levels decrease during REM sleep compared to wakefulness in rat medial prefrontal cortex29. Dopamine levels in rat medial prefrontal cortex also vary across the sleep wake cycle such that dopamine levels are greater during the electroencephalographically (EEG) activated states of wakefulness and REM sleep compared to the EEG deactivated state of NREM sleep29. In the locus coeruleus and amygdala the release of norepinephrine and serotonin decreases with sleep whereas dopamine release does not change, demonstrating that neurochemical changes during sleep are neurotransmitter and brain region dependent30.

The elimination of waking consciousness by propofol may be due, in part, to suppression of monoaminergic transmission in multiple arousal promoting brain regions. Dopamine levels in the nucleus accumbens are greater during wakefulness and REM sleep29 than during NREM sleep, and propofol decreases dopamine release in the nucleus accumbens31,32. However, propofol increases dopamine and serotonin metabolites in rat somatosensory cortex33. This finding suggests that propofol increases the release of these transmitters in rat somatosensory cortex. Dopamine and serotonin each can cause excitation or inhibition, depending upon the type of receptor they activate. Thus, it will be important to combine electrophysiological and neurochemical studies to provide a complete understanding of the effects of anesthetics on monoaminergic neurotransmission in specific brain regions.

Systemic administration of epinephrine, norepinephrine, and dopamine decreases arterial blood propofol concentrations and increase cardiac output in sheep under continuous propofol infusion, suggesting that monoamines can reverse propofol anesthesia by altering circulation34. Systemic administration of the alpha2 receptor agonist clonidine to rats increases the duration of anesthesia produced by propofol and decreases prefrontal cortex norepinephrine release35. This same study also found that systemic administration of the alpha2 receptor antagonist yohimbine decreases the duration of propofol anesthesia and increases cortical norepinephrine release. Given the important role of monoamines in promoting wakefulness, a productive area for future studies will be to determine whether propofol inhibits monoaminergic neurotransmission in the prefrontal cortex and the locus coeruleus. The mechanisms of anesthetic action, similar to the neurobiology of sleep, will be better understood as the effects of anesthetics on neurotransmission are elucidated on a brain region-by-region basis.

1.2 GABA

GABA is an inhibitory amino acid involved in actively generating sleep25 and anesthesia36. The GABAA receptor is made up of 5 subunits. The alpha, beta, and gamma subunits all have been shown to be involved in the regulation of sleep and anesthesia. Most GABAA receptors are composed of 2 alpha, 2 beta, and 1 gamma subunit37. The combination of receptor subtypes that comprise the GABAA receptor varies in different brain regions and may account for differential effects of drugs in each region (reviewed in38). For example, the ability of propofol to activate GABAA receptors varies with the type of alpha subunit (alpha1 versus alpha6)39. The endogenous molecule GABA and the anesthetic propofol act at different subtypes of the GABAA receptor beta2 subunit (MW 54 versus 56 kDa) to produce differential effects on naturally occurring sleep versus anesthesia40.

Administration of GABAA receptor agonists or antagonists to brain regions regulating states of consciousness can either increase or decrease wakefulness, depending on the brain region into which the drugs are administered. For example, enhancing GABAergic inhibition in brain regions that promote arousal, such as the posterior hypothalamus, locus coeruleus, and dorsal raphe nucleus, produces sleep (reviewed in12). In contrast, administering GABAmimetics into the pontine reticular formation increases wakefulness and decreases sleep41-43. Anesthetics enhance GABAergic neurotransmission by increasing chloride ion conductance and causing neuronal hyperpolarization (reviewed in38). In the brain stem locus coeruleus and dorsal raphe nucleus, GABA levels are highest during REM sleep44 and, as noted above, electrophysiological data show that locus coeruleus and dorsal raphe neurons cease firing during REM sleep (reviewed in25). Propofol acting at GABAA receptors inhibits the firing of locus coeruleus neurons45. The time to propofol-induced loss of righting, used as a measure of sedation, is reduced by microinjecting a GABAA receptor antagonist into the tuberomammillary nucleus of the hypothalamus, a wakefulness promoting brain region14. This finding suggests that propofol causes its sedative effects, in part, by potentiating GABAergic inhibition of hypothalamic neurons that promote wakefulness. Similarly, intravenous administration of gabazine and picrotoxin, which block transmission at GABAA receptors, causes large increases in the ED50 for propofol induced immobility in rat46. These findings support the interpretation that immobility caused by propofol is mediated by GABAA receptors.

Propofol decreases regional cerebral glucose metabolism in rat47 and human48, and the extent of this depression varies by brain region. In humans, regional cerebral glucose metabolism in the cortex showed greater depression than in subcortical areas and the greatest depression within the cortex occurred in the left anterior cingulate and inferior colliculus48. Propofol enhances GABAergic neurotransmission49 and the glucose metabolism data correlate with the high benzodiazepine receptor density in human cerebral cortex50. The brain regions in which propofol selectively alters cerebral metabolism provide targets for further localization of function studies aiming to identify the mechanisms by which propofol produces anesthesia.

1.3 Glutamate

There is considerable evidence that excitatory amino acids contribute to the regulation of both sleep- and anesthesia-induced losses of waking consciousness. Glutamatergic transmission in many brain regions is important for sleep and anesthesia. In the brainstem, the laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei contain neurons that contribute to REM sleep generation (reviewed in12). Microinjection of glutamate into the PPT induces waking and/or REM sleep depending on the concentration of injected glutamate51. Glutamate levels in the PPT are greater during wakefulness than during NREM sleep or REM sleep52, consistent with the interpretation that glutamate in the LDT and PPT promotes arousal. Further evidence that glutamate promotes wakefulness is shown by systemic administration of the glutamate receptor antagonist riluzole which increases NREM sleep and REM sleep in rats53. However, intracerebroventricular administration of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonists MK-801 and AP5 decreases REM sleep but does not change NREM sleep or wakefulness54. The present search of the literature identified no studies that quantified the effect of propofol on brainstem levels of glutamate.

Available data demonstrate that the role of glutamate in the regulation of consciousness also varies as a function of brain region. In one study, glutamate levels in the orbitofrontal cortex of rat were highest during REM sleep, decreased during wakefulness, and lowest during NREM sleep55. These data are consistent with the interpretation that glutamate promotes an activated cortical EEG. Glutamate levels did not change in the prefrontal cortex during NREM sleep and REM sleep compared to levels during wakefulness29, suggesting that cortical glutamate is not involved in sleep regulation. REM sleep deprivation in the rat increased cortical glutamate levels56 alternatively implying that glutamate in the cortex is somehow involved in the regulation of sleep. In the basal forebrain, microinjection of the glutamate receptor agonists NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) increased wakefulness and gamma (30-60 Hz) EEG activity and decreased delta (1-4 Hz) EEG activity57. Microinjection of NMDA and AMPA into the cholinergic cell area of the basal forebrain also caused C-fos activation, a widely used marker of neuronal activity57. These results are consistent with the interpretation that glutamate in the basal forebrain promotes waking consciousness.

Data from many species and brain regions demonstrate that propofol decreases presynaptic, sodium channel-dependent, glutamate release in cortical, striatal, and hippocampal synaptosomes isolated from rats, mice, and guinea pigs58,59. Only one study showed that propofol did not change presynaptic glutamate uptake, binding, or transport in rat cortical isolated nerve terminal preparations60. Another study by the same group demonstrated that propofol did inhibit calcium dependent evoked glutamate release in rat cortical synaptosomes61. Considered together, these data suggest that propofol depresses glutamate neurotransmission but the exact mechanism has yet to be elucidated.

Both NMDA and AMPA receptors are important for the regulation of sleep, but only NMDA receptors contribute to the inhibition of currents in cultured mouse hippocampal neurons by propofol62. This inhibition occurs by allosteric modulation of the channel versus blockade of the channel. The literature search did not reveal any studies that have characterized the effect of propofol on metabotropic glutamate receptors. An exciting opportunity for future studies is to elucidate the role of glutamate in the neurochemical regulation of consciousness.

1.4 ACh

There is a long-standing appreciation that cholinergic neurotransmission contributes to the loss of consciousness associated with sleep and anesthesia8,63. Pontine ACh contributes to the generation of REM sleep and ACh release within the pontine reticular formation is greater during REM sleep than during NREM sleep and wakefulness64. The clinical finding that the acetylcholinesterase inhibitor physostigmine reverses propofol sedation suggests that propofol produces unconsciousness, in part, by disrupting cholinergic neurotransmission13. REM sleep, like wakefulness, is a brain activated state that is characterized by increases in cholinergic neurotransmission. Brain activated states of consciousness, such as wakefulness and REM sleep, are promoted by drugs that enhance cholinergic neurotransmission. Thus, the finding that physostigmine causes arousal from propofol sedation in humans13 is consistent with data showing that administering neostigmine or carbachol into the pontine reticular formation causes a REM sleep-like state in mouse65, rat66, and cat67.

The foregoing gain-of-function data illustrated by manipulations that increase ACh are complimented by loss-of-function studies that chemically eliminate cholinergic neurons. For example, the immunotoxin 192 IgG-Saporin selectively destroys basal forebrain cholinergic neurons. In rat, intracerebroventricular administration of 192 IgG-Saporin caused a reduction in ACh levels in frontoparietal cortex and hippocampus and a decrease in propofol-induced locomotor inhibition16. These findings suggest that inhibition of basal forebrain cholinergic neurons contributes to the hypnotic effect of propofol16. Results from this study are also consistent with the notion that anesthetics act in a brain site specific manner, because acetylcholine levels in the striatum and cerebellum were not reduced by treatment with 192 IgG-Saporin. The cerebellum and striatum are not brain regions with primary arousal state regulating functions.

Both muscarinic and nicotinic ACh receptors are important for the regulation of sleep and wakefulness. In vitro studies show that propofol blocks ACh-induced muscarinic M1 receptor currents68. Propofol also inhibits nicotinic ACh receptor mediated currents when the nicotinic receptor is composed of the alpha4 beta2 subunit but not the alpha7 homomeric subunit69,70. ACh release within the cerebral cortex and dorsal hippocampus is greater during wakefulness and REM sleep than during NREM sleep71. Propofol decreased ACh release in rat frontal cortex and hippocampus72, providing additional support for the conclusion that propofol causes sedation, in part, by inhibiting cholinergic neurotransmission in brain regions that regulate arousal.

1.5 Adenosine

Consistent with the idea that the neuronal circuits controlling sleep are preferentially modulated by anesthetics7, local administration of propofol to the medial preoptic area, a region known to promote sleep25, decreased latency to sleep onset, increased NREM sleep, and increased total sleep time73. The idea that neuronal networks that generate sleep also regulate anesthesia suggests the possibility that prior sleep history may affect anesthetic action. However, no clinical studies have demonstrated any difference in anesthetic requirement that is dependent on sleep deprivation. Preclinical studies have shown that sleep deprivation can enhance the sedative effects of propofol. Rats were sleep deprived for 24 h and then administered propofol anesthesia. Although loss of righting response is not identical to sleep, sleep deprivation decreased the latency for and prolonged the duration of loss of righting response caused by propofol74. These results also support the view that propofol acts at circuits involved in sleep regulation.

Adenosine is a sleep promoting neuromodulator that acts through 4 G protein coupled receptor subtypes, A1, A2A, A2B, and A3. During prolonged wakefulness brain adenosine levels increase within the basal forebrain and cortex75. The ability of sleep deprivation to decrease loss of righting response in rat was partially reversed by administration of adenosine A1 and A2A receptor antagonists17. Adenosine is known to inhibit excitatory neurotransmission through adenosine A1 receptors76. In another study, rats were sleep deprived for 24 h and then allowed to have 6 h of ad libitum sleep or 6 h of propofol anesthesia. Rats that experienced ad libitum sleep and propofol anesthesia had similar amounts of NREM sleep and REM sleep77. The authors interpreted these results to suggest that propofol anesthesia provides some of the restorative processes that take place during naturally occurring sleep.

2. Ketamine

Ketamine was first tested clinically in the mid 1960s78,79. The term dissociative anesthetic was introduced at that time, and referred to the findings that during treatment with ketamine, sensory information appeared to reach the sensory cortex but was not accurately perceived due to depression of cortical association areas78. Thus, ketamine caused a dissociation between nociceptive input and the subjective experience of nociception. Ketamine is a phencyclidine derivative that produces analgesia and amnesia without causing a complete loss of consciousness26,80,81. The primary mechanism of ketamine anesthesia is by antagonism of NMDA receptors82. Through NMDA receptor blockade, ketamine alters the actions of several arousal state related neurotransmitters, as outlined below.

2.1 Monoamines

Emergence from ketamine anesthesia is often characterized by confusion, agitation, visual hallucinations, and delirium82. This psychomimetic response has been well-investigated in the context of schizophrenia research83-86. Psychotic-like symptoms occurring during ketamine emergence may result from ketamine induced increases in dopamine release, particularly in the cerebral cortex. Subanesthetic doses of ketamine increase the release of dopamine and serotonin in rat prefrontal cortex87,88 and increase dopamine release in rat nucleus accumbens89. Increased dopamine release in the nucleus accumbens may contribute to the addictive properties of ketamine89. Brain imaging of healthy human volunteers showed that subanesthetic doses of ketamine decreased the binding of a dopamine D2/D3 receptor agonist in the posterior cingulate and retrosplenial cortices83. This decrease in agonist binding was most likely due to a ketamine induced increase in dopamine release, as ketamine increases cortical dopamine release in rat83,85.

Dopamine receptor subtypes contribute to the emergence responses to ketamine. Subanesthetic doses of ketamine in rodents cause hyperlocomotor activity characterized by staggering and stereotypic head-wagging. These behavioral responses to ketamine are reduced in dopamine D1A receptor knockout mice, suggesting a role for the dopamine D1 receptor in mediating emergence responses to ketamine90. Studies using in vitro expression systems for dopamine D2 receptors or rat membrane preparations have found conflicting results. One study showed that ketamine has high affinity for dopamine D2 receptors91, whereas another study found that ketamine does not cause functional responses via the dopamine D2 receptor92. In vivo binding studies in humans using PET imaging have suggested that subanesthetic doses of ketamine increase dopamine D2 receptor binding in the striatum but not the cerebellum86, whereas similar studies using a different ligand in monkeys showed no ketamine induced change in D2 receptor binding in the basal ganglia or cerebellum93. As noted repeatedly throughout this chapter, the brain region where anesthetic induced changes in neurotransmission occur is key to determining the response and the relevance to anesthetic mechanisms of action. Changes in dopamine levels in the cerebral cortex are much more likely to alter mental state than are changes in dopamine levels within the striatum or cerebellum.

Studies using in vitro expression systems of monoamine transmitters indicated that ketamine causes a direct inhibition of monoamine transporters, which would enhance monoaminergic effects and provide an additional mechanism underlying the ketamine emergence reaction94. Dopamine transporters, but not norepinephrine or serotonin transporters, are selectively inhibited by the S(+)-isomer of ketamine94. In vivo studies have shown that ketamine increases norepinephrine release in rat medial prefrontal cortex95. Norepinephrine release is normally greater during wakefulness than during physiological sleep, thus the ketamine-induced increase in norepinephrine may account for some of the dissociative properties of ketamine.

2.2 GABA

Ketamine has been shown to have some effects on GABAergic neurotransmission, but as of yet it is unclear if ketamine-induced alterations in GABAergic transmission are related to the mechanism of ketamine anesthesia. In vivo studies report that systemic administration of the GABAA receptor agonist muscimol potentiates ketamine-induced loss of righting response, and coadministration of the GABAA receptor antagonist bicuculline with ketamine antagonizes ketamine-induced loss of righting96. Data from other studies suggest that these responses are mediated indirectly. For example, studies using in vitro expression systems have shown that at clinically relevant concentrations, ketamine does not modulate recombinant GABAA receptor activity97. Furthermore, the GABAA receptor antagonists picrotoxin and gabazine cause only a small increase in the ED50 for ketamine induced inhibition of mobility in response to a noxious stimulus, suggesting an indirect role of GABAA receptors46. Finally, acute and chronic systemic administration of ketamine does not change GABA levels in rat medial prefrontal cortex87.

2.3 Glutamate

Ketamine is a noncompetitive NMDA receptor antagonist and the anesthetic effects of ketamine are thought to result primarily from NMDA receptor blockade. For example, the ketamine induced increase in dopamine release (discussed above in the section on monoamines83,85,87,88 is mediated by NMDA receptors. Studies measuring glutamate show that chronic treatment with ketamine decreases cerebrospinal fluid glutamate levels in rats98. During cerebral ischemia glutamate transporters reverse and release glutamate into the extracellular space causing neuronal damage99. Intravenous anesthetics are thought to be neuroprotective by decreasing this glutamate release into the extracellular space99. In Chinese hamster ovary cells transfected with a cloned human glial glutamate transporter, ketamine decreased glutamate-induced outward currents suggesting that ketamine modulates glutamate transporters in vitro99. Many studies have investigated the role of glutamatergic signaling and the dissociative state that is produced by ketamine anesthesia. Ketamine increases glutamate release in the nucleus accumbens100 and prefrontal cortex of rat88. Ketamine also increases anterior cingulate glutamate activity in humans101. These region-specific increases in glutamate likely account for some of the dissociative properties produced by ketamine anesthesia.

2.4 ACh

Ketamine modulates cholinergic neurotransmission in multiple brain regions and at both muscarinic and nicotinic cholinergic receptors. Many studies have demonstrated that ketamine is a noncompetitive inhibitor at nicotinic ACh receptors70,102. The inhibition of neuronal nicotinic ACh receptors by ketamine is subunit dependent, and nicotinic receptors that contain the beta1 versus beta2 subunit are more sensitive to ketamine103. Additionally, the presence of a single amino acid in the extracellular transmembrane region of the alpha7 subunit of nicotinic receptors determines whether ketamine can inhibit nicotinic receptor currents104. These data are consistent with the interpretation that ketamine produces anesthesia, in part, by modulating nicotinic ACh receptors. The story is complicated, however, because the S enantiomer of ketamine is three times more potent than the R enantiomer, yet in vitro the two enantiomers inhibit neuronal nicotinic ACh receptor currents equally105. In contrast to the prior study, these data suggest that the anesthetic effects of ketamine are unlikely to be mediated primarily through nicotinic receptor signaling105. Another mechanism by which ketamine might modulate cholinergic neurotransmission is through muscarinic ACh receptors. Fewer studies have investigated the effects of ketamine on the five subtypes of muscarinic cholinergic receptors. Ketamine has been shown to inhibit M1 muscarinic ACh receptor currents in vitro106. Consistent with the idea that ketamine anesthesia modulates cholinergic neurotransmission, repeated administration of ketamine causes up regulation of muscarinic cholinergic receptors in the forebrain107.

Several studies have determined the effect of ketamine on brain ACh release in vivo. Two studies demonstrated that systemically administered ketamine increased frontal108 and prefrontal109 ACh release in rat. These data are difficult to interpret relative to the present chapter because cortical ACh promotes waking consciousness. As noted above, ketamine is a dissociative anesthetic and the increase in cortical ACh release may contribute to the ability of ketamine to activate the bispectral index110. Intravenous delivery of ketamine as well as local ketamine administration to cat pontine reticular formation decreases ACh release and inhibits REM sleep80. The finding that ketamine increases ACh release in cortex108,109 and decreases ACh release in the reticular formation80 again emphasizes that efforts to elucidate the neurochemical regulation of sleep and anesthesia can anticipate results to vary as a function of brain region. Thus, we consider the postulate of a single “anesthesia center” in the brain to be an unhelpful throwback to the hope for a single, unifying mechanism.

2.5 Adenosine

Only one study was identified that investigated the role of adenosine in the mechanism of action of ketamine. That study found that an adenosine A2A receptor agonist blocked ketamine induced hyperactivity, suggesting that adenosine or adenosine receptors may somehow contribute to ketamine induced locomotor activation111. Adenosine is an important modulator of physiological sleep and alertness during wakefulness, and future studies examining the effects of ketamine on the actions of adenosine in the basal forebrain and prefrontal cortex are likely to contribute to a mechanistic understanding of ketamine induced alterations in arousal state.

II. Volatile Anesthetics Alter Neurotransmitters that Regulate Sleep and Wakefulness

This section selectively highlights the effects of isoflurane and sevoflurane, the most studied and widely used inhaled anesthetics (Table 2), on endogenous sleep-related molecules that include monoamines, ACh, GABA, glutamate, and adenosine.

3. Isoflurane

Ether, nitrous oxide, and chloroform were among the first molecules recognized for their anesthetic properties during the 1840s. Isoflurane, a halogenated ether, was developed in 1965 and entered clinical practice in the late 1970s112. Isoflurane binds to a specific site on the GABAA receptor to enhance neuronal inhibition. Additionally, isoflurane alters neurotransmission by varying the effects of many other sleep-regulating neuromodulators. Whether the effects of isoflurane on the transmitter systems discussed below are direct or indirect remains to be determined.

3.1 Monoamines

Few studies have investigated the role of serotonergic neurotransmission in isoflurane anesthesia. The medullary hypoglossal nucleus innervates the genioglossal muscles of the tongue and genioglossal muscles can obstruct patency of the airway. Endogenous serotonin excites hypoglossal neurons113 and isoflurane depresses the excitatory effect of serotonin on hypoglossal motoneurons in dogs114. Isoflurane also decreases hippocampal serotonin levels in wild type and serotonin transporter knockout mice115. These results indicate that the mechanism by which isoflurane decreases hippocampal serotonin levels is independent of the serotonin transporter. Decreases in serotonin levels persisted for several hours after cessation of isoflurane115. Hippocampal serotonin contributes to cognition and affect, and these data encourage additional studies to determine if isoflurane-induced decreases in hippocampal serotonin cause subsequent behavioral consequences.

Nitrous oxide and isoflurane are commonly coadministered and nitrous oxide produces analgesia, in part, by altering norepinephrine release in the spinal cord. Electrophysiological data show that isoflurane and norepinephrine each enhanced inhibitory postsynaptic currents in rat substantia gelatinosa neurons116. Coadministration of isoflurane and norepinephrine produced a greater increase in inhibitory postsynaptic currents than either drug alone, suggesting that isoflurane may produce analgesia, in part, by modulating norepinephrine neurotransmission at the level of the spinal cord dorsal horn116.

The preoptic area of the hypothalamus contains NREM sleep promoting neurons and is important for thermoregulation (reviewed in117). General anesthetics disrupt thermoregulatory control by neural mechanisms that remain unclear. Isoflurane increases preoptic area norepinephrine release in rat brain slices, suggesting that enhanced norepinephrine signaling in the hypothalamus may contribute to hypothermia during isoflurane anesthesia118.

Histaminergic neurons in the tuberomammillary nucleus of the posterior hypothalamus are an important component of wakefulness promoting neuronal systems (reviewed in119). However, few studies have investigated the effects of volatile anesthetics on histaminergic neurotransmission. One study investigated histamine metabolism in rat hypothalamus and found that isoflurane altered histamine turnover differentially in the anterior versus the posterior hypothalamus120. Isoflurane was shown to increase histamine levels by inhibiting histamine degradation in both the anterior and posterior hypothalamus. However, histamine degradation was increased during the post-isoflurane recovery period only in the posterior hypothalamus120. The post-anesthesia increase in histamine turnover within the posterior hypothalamus is consistent with the wakefulness promoting role of both histamine and the posterior hypothalamus. In contrast, the anterior hypothalamus contains sleep promoting GABAergic neurons that do not respond to histamine121. These data showing brain region specific effects of isoflurane on histamine metabolism120 encourage future studies examining the effects of isoflurane on synaptic transmission within the anterior and posterior hypothalamus. Such studies can be expected to yield mechanistic insights into how anesthetics alter states of consciousness.

Dopamine is wakefulness promoting in animals and in humans12. For example, intracerebroventricular administration of dopamine D1 and D2 receptor agonists during physiological sleep in rats causes an increase in wakefulness, an increase in motor activity, and a decrease in sleep122. Isoflurane increases basal dopamine release and dopamine metabolites in rat striatum in vivo123,124,125 and in rat striatal slices ex vivo125. Dopamine transporter knock out mice show an increase in wakefulness and a decrease in NREM sleep126. Positron emission tomography studies in rhesus monkey127 and in human128 demonstrated that dopamine transporter binding in the striatum decreases during isoflurane anesthesia. These studies suggest that isoflurane increases dopamine levels by inhibiting dopamine reuptake. In vitro experiments confirm that isoflurane causes internalization of the dopamine transporter129.

Emergence from anesthesia can be associated with an excitatory agitation phase, particularly in preschool children130. Striatal dopamine may contribute to this emergence reaction. In mice, recovery from isoflurane anesthesia is characterized by increased locomotor activity and increased dopamine turnover in the nucleus accumbens and striatum131. The importance of investigating these mechanisms in multiple brain regions is demonstrated by the fact that dopamine levels within the cortex and nucleus accumbens are greater during the activated states of wakefulness and REM sleep29, whereas dopamine levels in the locus coeruleus and amygdala do not change across the sleep wake cycle30.

3.2 GABA

GABAA receptors are an important target for inhalation anesthetics and contain a binding site for isoflurane132. Clinically relevant concentrations of isoflurane reduce the amplitude and extend the decay of GABA evoked currents by slowing the rate of GABA unbinding from recombinant GABAA receptors133. Isoflurane enhances GABAA receptor mediated currents in cultured rat cerebral cortical neurons134 and, at clinically relevant concentrations, inhibits both the release and reuptake of GABA in mouse cortical brain slices135. Isoflurane also increases the binding of the benzodiazepine receptor antagonist 11C-flumazenil to GABAA receptors in human cortex and cerebellum, as demonstrated by positron emission tomography136. Further evidence that isoflurane modulates GABAergic neurotransmission is demonstrated by the ability of an intrathecally administered GABAA receptor antagonist to increase the minimum alveolar concentration (MAC) value of isoflurane by 47% in rats137.

There have been few studies characterizing changes in endogenous GABA levels during states of sleep, wakefulness, or general anesthesia. GABA levels during sleep are increased above waking levels in cat dorsal raphe nucleus44, locus coeruleus138, and posterior hypothalamus139. These findings support the interpretation that GABAergic inhibition of these wakefulness promoting monoaminergic nuclei contributes to the generation of physiological sleep. Compared to waking levels, isoflurane has been shown to decrease GABA levels in rat basal forebrain and somatosensory cortex140. Preliminary data from cat also show that GABA levels in the substantia innominata region of the basal forebrain are lower during isoflurane anesthesia than during wakefulness141. GABAergic input to the cortex from the basal forebrain can cause excitation by inhibiting cortical inhibitory interneurons142-144. Thus, the isoflurane induced decrease in cortical GABA140 is consistent with the fact that isoflurane decreases cortical activation and slows the cortical EEG. Interestingly, isoflurane caused no change in posterior hypothalamic GABA levels140. Thus, even during states of general anesthesia there are brain site specific changes in GABAergic transmission.

The capability of isoflurane to produce anesthesia is dependent on the composition of GABAA receptor subunits. For example, a mutation in the alpha1 subunit of the GABAA receptor makes the receptor insensitive to isoflurane145. The ability of isoflurane to enhance GABA evoked GABAA receptor currents in cultured Sf9 cells is dependent on the presence of the gamma2s subunit146. GABA-mediated currents have been studied using an in vitro expression system transfected with recombinant GABAA receptors, and dual effects were reported147. At clinically relevant concentrations isoflurane was shown to potentiate GABA-mediated currents, and at higher concentrations isoflurane inhibited GABA currents147. The potentiating effects that predominate at lower concentrations are thought to be relevant for the mechanism of isoflurane action. Studies in rat indicate that spinal GABAA receptors can contribute to immobility caused by isoflurane148. The role of GABAA receptors in mediating immobility is not straight forward. For example, pharmacological blocking studies from this same group conclude that the immobilizing effect of isoflurane is not mediated by GABAA receptors46. Transgenic mice have been used in an effort to clarify which components of the GABAA receptor mediate immobility caused by isoflurane. Mice with a knock-in mutation in the beta3 subunit of the GABAA receptor are less sensitive to the immobilizing action of isoflurane149.

3.3 Glutamate

One mechanism by which isoflurane has been proposed to cause anesthesia is by inhibiting excitatory neurotransmission. Glutamate is the major excitatory amino acid transmitter in the brain, and the effects of glutamate can be reduced by decreasing its release, increasing its uptake, or blocking its receptors. Glutamate transporters are located on neurons and glia, and take up extracellular glutamate to regulate synaptic glutamate levels. Uptake is the major inactivation mechanism for glutamate, as it is not enzymatically degraded.

Isoflurane has been shown to reduce glutamate release in isolated nerve terminals derived from rat cortex, hippocampus, and striatum58,150. Isoflurane decreases glutamate release in rat hippocampal151 and cerebral cortex slices135. At greater concentrations, however, isoflurane also inhibits glutamate uptake135. The authors suggest that the effects of isoflurane depend upon a balance between inhibition of release and inhibition of reuptake135. Several other studies have shown that isoflurane increases glutamate uptake. In cultured rat glial cells, isoflurane increases glutamate uptake via glutamate transporters152 and in vivo inhibitors of glutamate transporters increase MAC for isoflurane in rat153. Isoflurane also increases glutamate uptake in rat cerebral cortex synaptosomes154. Five types of glutamate transporters have been identified, and isoflurane increases the expression and activity of glutamate type 3 transporters in cultured rat glioma cells155. Isoflurane causes phosphorylation of a serine residue to activate the glutamate type 3 transporter and redistribute it to the plasma membrane156.

Glutamate causes excitation by activating NMDA receptors, and NMDA receptor activation requires the binding of both glutamate and glycine. Isoflurane has recently been shown to inhibit NMDA receptors by binding to the glycine site157. This finding suggests that blocking the excitatory effects of glutamate at NMDA receptors may be one mechanism underlying the anesthetic and neuroprotective effects of isoflurane.

The above studies were performed using reduced preparations such as cell cultures, synaptosomes, or brain slices. Few in vivo studies using intact animals have determined the effects of isoflurane on glutamatergic transmission. In vivo microdialysis work using rat demonstrated that isoflurane differentially alters glutamate levels depending on brain region140. Compared to wakefulness, isoflurane causes a concentration dependent increase in glutamate levels in the basal forebrain, an increase in somatosensory cortex glutamate levels at one concentration only, and no effect on glutamate levels in the posterior hypothalamus140. The mechanistic implications of the surprising finding that isoflurane increases basal forebrain glutamate levels are not yet clear.

3.4 ACh

Isoflurane modulates nicotinic and muscarinic cholinergic receptors, and the release of ACh. Nicotinic receptors are comprised of five subunits, and several studies have investigated the role of various nicotinic ACh receptor subunits in the mechanism of action of volatile anesthetics158. Isoflurane at clinically relevant concentrations inhibits neuronal nicotinic ACh receptor currents expressed in vitro when the receptors contain the alpha4-beta2 subunit combination159. Isoflurane does not block the response of homomeric alpha7 nicotinic receptors to ACh when the anesthetic and the agonist are coadministered69. However, clinically relevant concentrations of isoflurane do inhibit homomeric alpha7 nicotinic receptors when the anesthetic is applied prior to ACh, or when ACh is applied in high concentrations160. These findings may be relevant in vivo, because alpha7 nicotinic receptors do occur in brain160, and synaptic levels of neurotransmitters have been estimated to reach concentrations in the micromolar to millimolar range. The effects of isoflurane on native (i.e., non-recombinant) nicotinic receptors also have been investigated161. Interestingly, both isoflurane and a structurally similar halogenated molecule that does not cause immobility but does have amnestic properties inhibits native neuronal nicotinic ACh receptors in rat medial habenula neurons161. Another structurally similar agent with neither immobilizing nor amnestic properties does not block nicotinic receptor-mediated currents161. These data suggest that the amnestic effects of isoflurane may be mediated, in part, by nicotinic receptors in the medial habenula. More in vivo studies are needed to determine if nicotinic ACh receptors are relevant for the production of anesthesia by isoflurane.

There are five muscarinic cholinergic receptor subtypes, and isoflurane has been shown to inhibit M3 but not M1 muscarinic receptors162. M1 and M3 receptors are structurally quite similar, thus different effects of the same anesthetic on these two subtypes implies that the site of action is quite specific. More recently, the same investigators showed that isoflurane-induced inhibition of M3 receptor signaling is mediated by an increase in protein kinase C activity, but the site of action on the M3 receptor has not yet been localized163. Another study found that intracerebroventricular administration of the acetylcholinesterase inhibitor neostigmine or the muscarinic agonist oxotremorine to isoflurane anesthetized rats increases spontaneous limb and orofacial exploratory movements, indicating increased arousal10. Cholinergic activation during isoflurane anesthesia also activates the cortex, as indicated by an increase in cross-approximate entropy of the bihemispheric frontal EEG10. These data are consistent with the interpretation that activation of central cholinergic neurotransmission can reverse some aspects of isoflurane anesthesia.

Studies of intact brain using in vivo microdialysis report that isoflurane causes a dose dependent decrease in ACh release in rat cerebral cortex140,164, rat striatum164, and cat pontine reticular formation165. The effect of isoflurane on ACh release varies with age. Isoflurane causes a significantly larger decrease in prefrontal cortex ACh release in old versus young rats166. Future studies are needed to determine whether aged rats show performance or memory deficits following isoflurane anesthesia. Such a finding would support the interpretation that isoflurane-induced decreases in prefrontal cortex ACh release may contribute to increased post-operative delirium in the elderly.

3.5 Adenosine

Peroperative adenosine infusion in humans undergoing breast surgery decreases isoflurane requirement and decreases postoperative analgesic requirement167. A similar study of patients undergoing shoulder surgery showed that adenosine reduces the requirement for isoflurane but has no effect on postoperative analgesic requirement168. Although adenosine is well recognized to have antinociceptive effects169, few studies have examined the possible role of adenosine in mediating the anesthetic effects of isoflurane. In rat, isoflurane-induced reductions in focal cerebral ischemia are blocked by an adenosine A1 receptor antagonist, indicating that this neuroprotective effect of isoflurane may be mediated by adenosine A1 receptors170. Isoflurane-induced activation of adenosine A1 receptors in primary cultures of rat hippocampal neurons also suppresses spontaneous calcium oscillations171. This study suggests that another mechanism by which isoflurane may be neuroprotective is by increasing adenosine levels171.

4. Sevoflurane

Sevoflurane is a nonflammable halogenated ether. Sevoflurane is the newest inhalation anesthetic to be used in humans, and was introduced into clinical practice in the late 1980s. The effects of sevoflurane on sleep-related neurotransmitters and neuromodulators are discussed below.

4.1 Monoamines

Few studies have investigated the role of monoaminergic neurotransmission in sevoflurane anesthesia. Sevoflurane produces a higher incidence of agitation during emergence from anesthesia in children than other general anesthetics 130,172. Alpha2 adrenergic agonists, such as dexmedetomidine, decrease the frequency of emergence agitation by sevoflurane172, and alpha2 agonists inhibit the firing of noradrenergic locus coeruleus neurons173. Noradrenergic neurons in the locus coeruleus promote wakefulness (reviewed in25), and sevoflurane directly excites noradrenergic locus coeruleus neurons in rat174. Sevoflurane increases norepinephrine release in rat preoptic area 175. Taken together, these data support the interpretation that noradrenergic neurotransmission contributes to emergence agitation produced by sevoflurane. The monoamines dopamine and histamine also promote wakefulness (reviewed in25), and sevoflurane increases cortical dopamine release in rat brain slices by modulating dopamine transporters176. Sevoflurane also increases hypothalamic histamine levels in rat by inhibiting histamine metabolism120.

4.2 GABA

Sevoflurane, similar to many anesthetic molecules, enhances transmission at GABAA receptors. Using recombinant alpha1, beta2, gamma2 GABAA receptors, isoflurane has been shown to increase the affinity of GABA and cause an open-channel block at the GABAA receptor177. These data suggest sevoflurane increases GABAergic transmission by binding to at least two different sites on GABAA receptors177. Sevoflurane also promotes GABA evoked GABAA receptor chloride currents in isolated rat hippocampal neurons and modulates the GABA response by altering activation and decay phases of the current178. The modulation of hippocampal GABA receptors by sevoflurane is dependent on norepinephrine signaling, as coadministration of sevoflurane and norepinephrine have a large additive effect on inhibitory post synaptic currents and prolong the decay of the current179. These results suggest that sevoflurane anesthesia is mediated, in part, by enhanced GABAergic neurotransmission. This interpretation awaits confirmation from in vivo studies.

4.3 Glutamate

General anesthetics are thought to produce their effects by the dual actions of increasing inhibitory GABAergic neurotransmission and inhibiting excitatory glutamatergic neurotransmission. Sevoflurane has been shown to decrease calcium dependent glutamate release using synaptosomes isolated from human cerebral cortex180. Another study using rat cortical neurons also demonstrated that sevoflurane decreases glutamate release181. These data encourage additional experiments designed to determine whether the sevoflurane-induced decrease in glutamate release contributes to the anesthetic effects of sevoflurane in vivo.

4.4 ACh

Cholinergic neurotransmission is important for the regulation of sleep and waking consciousness, as well as anesthesia8,12. Nicotinic receptors are inhibited by several anesthetics69,158, including sevoflurane182. In humans, thalamocortical connectivity is suppressed when anesthetics induce loss of consciousness183. Nicotinic receptors are densely expressed throughout the human thalamus184, and microinjection of nicotine into rat central medial thalamus reverses the sevoflurane induced loss of righting response185. These data suggest that suppression of midline thalamic cholinergic neurons contribute to sevoflurane induced unconsciousness.

4.5 Adenosine

The PubMed review revealed no studies examining the role of adenosinergic neurotransmission in sevoflurane anesthesia.

III. Conclusions

A recurring theme that emerges from any consideration of anesthetic alterations in brain neurochemistry is that the direction and magnitude of chemical change varies as a function of brain region and anesthetic agent. There is no evidence that any single mechanism or brain region regulates the loss of waking consciousness during sleep or anesthesia. Even within seemingly homogenous states of consciousness, the brain reveals widely disparate levels of activation (reviewed in186-188). Such data make clear that understanding anesthetic alterations in consciousness will be limited unless the cellular and molecular mechanisms are elucidated on a brain region-by-region basis. Progress can be made if future studies include local delivery of anesthetic molecules along with measurement of endogenous neurotransmitters in specific brain regions. Another limitation concerns the lack of rigor regarding how anesthetic states of consciousness are classified. The terms loss of righting reflex, sleep, sedation, hypnosis, and sleep-time are often used casually to reach desired conclusions regarding anesthesia-induced alterations in consciousness. This lack of terminological rigor is particularly problematic for speculative extrapolations seeking to establish a link between pre-clinical studies and clinical implications. A formal and consistent classification of states based on physiological and behavioral traits189,190 is essential and clinically relevant191. Drugs which selectively suspend consciousness are a logical path to understanding the neurological substrate of consciousness192 and anesthesiology has unique potential to contribute to the clinical neuroscience of consciousness studies132,186,193. Finally, judgments concerning the status of consciousness studies for anesthesiology should be tempered by expectations that incorporate an evolutionary perspective. Neurochemical networks that evolved to generate the loss of waking consciousness during sleep are the most logical substrates through which anesthetic molecules eliminate waking consciousness. Continuing efforts by anesthesiologists to understand consciousness will be promoted by research paradigms that incorporate the specific brain regions and neurochemical modulators of sleep.

Acknowledgments

Grant sponsor: National Institutes of Health

Grant number: MH45361, HL40881, HL57120, HL65272

References

1. Blackmore SJ. Consciousness : an introduction. Oxford University Press; Oxford, New York: 2004.
2. Gallagher II. Philosophical conceptions of the self: implications for cognitive science. Trends Cogn Sci. 2000;4:14–21. [PubMed]
3. Koch C. The quest for consciousness : a neurobiological approach. Roberts and Co.; Denver, Colo.: 2004.
4. Hobson JA, Pace-Schott EF, Stickgold R. Consciousness: Its vicissitudes in waking and sleep: An integration of recent neurophysiological and neuropsychological evidence. In: Gazzaniga M, editor. The New Cognitive Neurosciences. 2nd. MIT Press; Cambridge, MA: 1999.
5. Hobson JA, Pace-Schott EF. The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci. 2002;3:679–693. [PubMed]
6. Hobson JA, Pace-Schott EF, Stickgold R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. Behav Brain Sci. 2000;23:793–842. [PubMed]
7. Lydic R. Reticular modulation of breathing during sleep and anesthesia. Curr Opin Pulm Med. 1996;2:474–481. [PubMed]
8. Lydic R, Baghdoyan HA. Cholinergic contributions to the control of consciousness. In: Yaksh TL, Lynch C, Zapol WM, et al., editors. Anesthesia: Biologic Foundations. Lippincott Raven; New York: 1998. pp. 433–450.
9. Fiset P. Research on anesthesia, consciousness or both? Understanding our anesthetic drugs and defining the neural substrate. Can J Anesth. 2003;50:R1–R5.
10. Hudetz AG, Wood JD, Kampine JP. Cholinergic reversal of isoflurane anesthesia in rats as measured by cross-approximate entropy of the electroencephalogram. Anesthesiology. 2003;99:1125–1131. [PubMed]
11. Kelz MB, Sun Y, Chen J, et al. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci USA. 2008;105:1309–1314. [PubMed]
12. Lydic R, Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology. 2005;103:1268–1295. [PubMed]
13. Meuret P, Backman SB, Bonhomme V, et al. Physostigmine reverses propofol-induced unconsciousness and attenuation of the auditory steady state response and bispectral index in human volunteers. Anesthesiology. 2000;93:708–717. [PubMed]
14. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci. 2002;5:979–984. [PubMed]
15. Nelson LE, Lu J, Guo T, et al. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003;98:428–436. [PubMed]
16. Pain L, Jeltsch H, Lehmann O, et al. Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats. Br J Anaesth. 2000;85:869–873. [PubMed]
17. Tung A, Herrera S, Szafran MJ, et al. Effect of sleep deprivation on righting reflex in the rat is partially reversed by administration of adenosine A1 and A2 receptor antagonists. Anesthesiology. 2005;102:1158–1164. [PubMed]
18. Yasuda Y, Takeda A, Fukuda S, et al. Orexin A elicits arousal electroencephalography without sympathetic cardiovascular activation in isoflurane-anesthetized rats. Anesth Analg. 2003;97:1663–1666. [PubMed]
19. Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008;9:370–386. [PubMed]
20. Massimini M, Ferrarelli F, Huber R, et al. Breakdown of cortical effective connectivity during sleep. Science. 2005;309:2228–2232. [PubMed]
21. Lydic R, Baghdoyan HA. Sleep and anesthesia. In: Hemmings HC, Hopkins PM, editors. Foundations of Anesthesia: Basic and Clinical Sciences. Mosby/Elsevier; Philadephia, PA: 2005. pp. 361–371.
22. Lydic R, Baghdoyan HA. Anesthesiology: relevance for sleep medicine. In: Lee-Chiong TL, editor. Encyclopedia of Sleep Medicine. John Wiley & Sons; Hoboken, New Jersey: 2005. pp. 927–932.
23. Tung A, Mendelson WB. Anesthesia and sleep. Sleep Med Rev. 2004;8:213–225. [PubMed]
24. Lydic R, Baghdoyan HA. Neurochemical mechanisms mediating opioid-induced REM sleep distruption. In: Lavigne G, Sessle BJ, Choinière M, et al., editors. Sleep and Pain. International Association for the Study of Pain (IASP) Press; Seattle: 2007. pp. 99–122.
25. Steriade M, McCarley RW. Brain Control of Wakefulness and Sleep. Second. Plenum Press; New York: 2005.
26. Reves JG, Glass PSA, Lubarsky DA, et al. Intravenous Nonopioid Anesthetics. In: Miller RD, editor. Miller's Anesthesia. Sixth. Elsevier Churchill Livingstone; Philadelphia, Pennsylvania: 2005. pp. 317–378.
27. Muzur A, Pace-Schott EF, Hobson JA. The prefrontal cortex in sleep. Trends Cogn Sci. 2002;6:475–481. [PubMed]
28. Bjorvatn B, Gronli J, Hamre F, et al. Effects of sleep deprivation on extracellular serotonin in hippocampus and frontal cortex of the rat. Neuroscience. 2002;113:323–330. [PubMed]
29. Lena I, Parrot S, Deschaux O, et al. Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep--wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res. 2005;81:891–899. [PubMed]
30. Shouse MN, Staba RJ, Saquib SF, et al. Monoamines and sleep: microdialysis findings in pons and amygdala. Brain Res. 2000;860:181–189. [PubMed]
31. Pain L, Gobaille S, Schleef C, et al. In vivo dopamine measurements in the nucleus accumbens after nonanesthetic and anesthetic doses of propofol in rats. Anesth Analg. 2002;95:915–919. [PubMed]
32. Schulte D, Callado LF, Davidson C, et al. Propofol decreases stimulated dopamine release in the rat nucleus accumbens by a mechanism independent of dopamine D2, GABAA and NMDA receptors. Br J Anaesth. 2000;84:250–253. [PubMed]
33. Shyr MH, Tsai TH, Yang CH, et al. Propofol anesthesia increases dopamine and serotonin activities at the somatosensory cortex in rats: a microdialysis study. Anesth Analg. 1997;84:1344–1348. [PubMed]
34. Myburgh JA, Upton RN, Grant C, et al. Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model. Intensive Care Med. 2001;27:276–282. [PubMed]
35. Kushikata T, Hirota K, Yoshida H, et al. Alpha-2 adrenoceptor activity affects propofol-induced sleep time. Anesth Analg. 2002;94:1201–1206. [PubMed]
36. Orser BA. Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs. J Clin Sleep Med. 2006;2:S12–18. [PubMed]
37. Bormann J. The ‘ABC’ of GABA receptors. Trends Pharmacol Sci. 2000;21:16–19. [PubMed]
38. Mody I, Pearce RA. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci. 2004;27:569–575. [PubMed]
39. Krasowski MD, O'Shea SM, Rick CE, et al. Alpha subunit isoform influences GABAA receptor modulation by propofol. Neuropharmacology. 1997;36:941–949. [PMC free article] [PubMed]
40. Bjornstrom K, Eintrei C. The difference between sleep and anaesthesia is in the intracellular signal: propofol and GABA use different subtypes of the GABAA receptor beta subunit and vary in their interaction with actin. Acta Anaesthesiol Scand. 2003;47:157–164. [PubMed]
41. Xi MC, Morales FR, Chase MH. Evidence that wakefulness and REM sleep are controlled by a GABAergic pontine mechanism. J Neurophysiol. 1999;82:2015–2019. [PubMed]
42. Sanford LD, Tang X, Xiao J, et al. GABAergic regulation of REM sleep in reticularis pontis oralis and caudalis in rats. J Neurophysiol. 2003;90:938–945. [PubMed]
43. Watson CJ, Soto-Calderon H, Lydic R, et al. Pontine reticular formation (PnO) administration of hypocretin-1 increases PnO GABA levels and wakefulness. Sleep. 2008;31:453–464. [PubMed]
44. Nitz D, Siegel J. GABA release in the dorsal raphe nucleus: role in the control of REM sleep. Am J Physiol. 1997;273:R451–455. [PubMed]
45. Chen CL, Yang YR, Chiu TH. Activation of rat locus coeruleus neuron GABAA receptors by propofol and its potentiation by pentobarbital or alphaxalone. Eur J Pharmacol. 1999;386:201–210. [PubMed]
46. Sonner JM, Zhang Y, Stabernack C, et al. GABAA receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner. Anesth Analg. 2003;96:706–712. [PubMed]
47. Dam M, Ori C, Pizzolato G, et al. The effects of propofol anesthesia on local cerebral glucose utilization in the rat. Anesthesiology. 1990;73:499–505. [PubMed]
48. Alkire MT, Haier RJ, Barker SJ, et al. Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. Anesthesiology. 1995;82:393–403. [PubMed]
49. Peduto VA, Concas A, Santoro G, et al. Biochemical and electrophysiologic evidence that propofol enhances GABAergic transmission in the rat brain. Anesthesiology. 1991;75:1000–1009. [PubMed]
50. Braestrup C, Albrechtsen R, Squires RF. High densities of benzodiazepine receptors in human cortical areas. Nature. 1977;269:702–704. [PubMed]
51. Datta S, Spoley EE, Patterson EH. Microinjection of glutamate into the pedunculopontine tegmentum induces REM sleep and wakefulness in the rat. Am J Physiol Regul Integr Comp Physiol. 2001;280:R752–759. [PubMed]
52. Kodama T, Honda Y. Acetylcholine and glutamate release during sleep-wakefulness in the pedunculopontine tegmental nucleus and norepinephrine changes regulated by nitric oxide. Psychiatry Clin Neurosci. 1999;53:109–111. [PubMed]
53. Stutzmann JM, Lucas M, Blanchard JC, et al. Riluzole, a glutamate antagonist, enhances slow wave and REM sleep in rats. Neurosci Lett. 1988;88:195–200. [PubMed]
54. Prospero-Garcia O, Criado JR, Henriksen SJ. Pharmacology of ethanol and glutamate antagonists on rodent sleep: a comparative study. Pharmacol Biochem Behav. 1994;49:413–416. [PubMed]
55. Lopez-Rodriguez F, Medina-Ceja L, Wilson CL, et al. Changes in extracellular glutamate levels in rat orbitofrontal cortex during sleep and wakefulness. Arch Med Res. 2007;38:52–55. [PubMed]
56. Bettendorff L, Sallanon-Moulin M, Touret M, et al. Paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex. Sleep. 1996;19:65–71. [PubMed]
57. Cape EG, Jones BE. Effects of glutamate agonist versus procaine microinjections into the basal forebrain cholinergic cell area upon gamma and theta EEG activity and sleep-wake state. Eur J Neurosci. 2000;12:2166–2184. [PubMed]
58. Lingamaneni R, Birch ML, Hemmings HC., Jr Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol. Anesthesiology. 2001;95:1460–1466. [PubMed]
59. Ratnakumari L, Hemmings HC., Jr Effects of propofol on sodium channel-dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes. Anesthesiology. 1997;86:428–439. [PubMed]
60. Westphalen RI, Hemmings HC., Jr Effects of isoflurane and propofol on glutamate and GABA transporters in isolated cortical nerve terminals. Anesthesiology. 2003;98:364–372. [PubMed]
61. Westphalen RI, Hemmings HC., Jr Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals. J Pharmacol Exp Ther. 2003;304:1188–1196. [PubMed]
62. Orser BA, Bertlik M, Wang LY, et al. Inhibition by propofol (2,6 di-isopropylphenol) of the N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol. 1995;116:1761–1768. [PMC free article] [PubMed]
63. Backman SB, Fiset P, Plourde G. Cholinergic mechanisms mediating anesthetic induced altered states of consciousness. Prog Brain Res. 2004;145:197–206. [PubMed]
64. Leonard TO, Lydic R. Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate. J Neurosci. 1997;17:774–785. [PubMed]
65. Lydic R, Douglas CL, Baghdoyan HA. Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing. Sleep. 2002;25:835–841. [PubMed]
66. Bourgin P, Escourrou P, Gaultier C, et al. Induction of rapid eye movement sleep by carbachol infusion into the pontine reticular formation in the rat. Neuroreport. 1995;6:532–536. [PubMed]
67. Baghdoyan HA, Monaco AP, Rodrigo-Angulo ML, et al. Microinjection of neostigmine into the pontine reticular formation of cats enhances desynchronized sleep signs. J Pharmacol Exp Ther. 1984;231:173–180. [PubMed]
68. Nagase Y, Kaibara M, Uezono Y, et al. Propofol inhibits muscarinic acetylcholine receptor-mediated signal transduction in Xenopus Oocytes expressing the rat M1 receptor. Jpn J Pharmacol. 1999;79:319–325. [PubMed]
69. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology. 1997;86:859–865. [PubMed]
70. Furuya R, Oka K, Watanabe I, et al. The effects of ketamine and propofol on neuronal nicotinic acetylcholine receptors and P2x purinoceptors in PC12 cells. Anesth Analg. 1999;88:174–180. [PubMed]
71. Marrosu F, Portas C, Mascia MS, et al. Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep-wake cycle in freely moving cats. Brain Res. 1995;671:329–332. [PubMed]
72. Kikuchi T, Wang Y, Sato K, et al. In vivo effects of propofol on acetylcholine release from the frontal cortex, hippocampus and striatum studied by intracerebral microdialysis in freely moving rats. Br J Anaesth. 1998;80:644–648. [PubMed]
73. Tung A, Bluhm B, Mendelson WB. The hypnotic effect of propofol in the medial preoptic area of the rat. Life Sci. 2001;69:855–862. [PubMed]
74. Tung A, Szafran MJ, Bluhm B, et al. Sleep deprivation potentiates the onset and duration of loss of righting reflex induced by propofol and isoflurane. Anesthesiology. 2002;97:906–911. [PubMed]
75. Basheer R, Strecker RE, Thakkar MM, et al. Adenosine and sleep-wake regulation. Prog Neurobiol. 2004;73:379–396. [PubMed]
76. Tohdoh Y, Narimatsu E, Kawamata M, et al. The involvement of adenosine neuromodulation in pentobarbital-induced field excitatory postsynaptic potentials depression in rat hippocampal slices. Anesth Analg. 2000;91:1537–1541. [PubMed]
77. Tung A, Bergmann BM, Herrera S, et al. Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology. 2004;100:1419–1426. [PubMed]
78. Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45:29–40. [PubMed]
79. Domino EF, Chodoff P, Corssen G. Pharmacologic Effects of Ci-581, a New Dissociative Anesthetic, in Man. Clin Pharmacol Ther. 1965;6:279–291. [PubMed]
80. Lydic R, Baghdoyan HA. Ketamine and MK-801 decrease acetylcholine release in the pontine reticular formation, slow breathing, and disrupt sleep. Sleep. 2002;25:617–622. [PubMed]
81. White PF, Way WL, Trevor AJ. Ketamine--its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–136. [PubMed]
82. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87:1186–1193. [PubMed]
83. Aalto S, Ihalainen J, Hirvonen J, et al. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl) 2005;182:375–383. [PubMed]
84. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48:627–640. [PubMed]
85. Moghaddam B, Adams B, Verma A, et al. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–2927. [PubMed]
86. Smith GS, Schloesser R, Brodie JD, et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology. 1998;18:18–25. [PubMed]
87. Lindefors N, Barati S, O'Connor WT. Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex. Brain Res. 1997;759:205–212. [PubMed]
88. Lorrain DS, Baccei CS, Bristow LJ, et al. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience. 2003;117:697–706. [PubMed]
89. Masuzawa M, Nakao S, Miyamoto E, et al. Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study. Anesth Analg. 2003;96:148–152. [PubMed]
90. Miyamoto S, Mailman RB, Lieberman JA, et al. Blunted brain metabolic response to ketamine in mice lacking D1A dopamine receptors. Brain Res. 2001;894:167–180. [PubMed]
91. Kapur S, Seeman P. Ketamine has equal affinity for NMDA receptors and the high-affinity state of the dopamine D2 receptor. Biol Psychiatry. 2001;49:954–957. [PubMed]
92. Jordan S, Chen R, Fernalld R, et al. In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors. Eur J Pharmacol. 2006;540:53–56. [PubMed]
93. Nader MA, Grant KA, Gage HD, et al. PET imaging of dopamine D2 receptors with [18F]fluoroclebopride in monkeys: effects of isoflurane- and ketamine-induced anesthesia. Neuropsychopharmacology. 1999;21:589–596. [PubMed]
94. Nishimura M, Sato K. Ketamine stereoselectively inhibits rat dopamine transporter. Neurosci Lett. 1999;274:131–134. [PubMed]
95. Kubota T, Anzawa N, Hirota K, et al. Effects of ketamine and pentobarbital on noradrenaline release from the medial prefrontal cortex in rats. Can J Anaesth. 1999;46:388–392. [PubMed]
96. Irifune M, Sato T, Kamata Y, et al. Evidence for GABAA receptor agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice. Anesth Analg. 2000;91:230–236. [PubMed]
97. Flood P, Krasowski MD. Intravenous anesthetics differentially modulate ligand-gated ion channels. Anesthesiology. 2000;92:1418–1425. [PubMed]
98. Tomiya M, Fukushima T, Kawai J, et al. Alterations of plasma and cerebrospinal fluid glutamate levels in rats treated with the N-methyl-D-aspartate receptor antagonist, ketamine. Biomed Chromatogr. 2006;20:628–633. [PubMed]
99. Sakai F, Amaha K. Midazolam and ketamine inhibit glutamate release via a cloned human brain glutamate transporter. Can J Anaesth. 2000;47:800–806. [PubMed]
100. Razoux F, Garcia R, Lena I. Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology. 2007;32:719–727. [PubMed]
101. Rowland LM, Bustillo JR, Mullins PG, et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry. 2005;162:394–396. [PubMed]
102. Coates KM, Flood P. Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes. Br J Pharmacol. 2001;134:871–879. [PMC free article] [PubMed]
103. Yamakura T, Chavez-Noriega LE, Harris RA. Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine. Anesthesiology. 2000;92:1144–1153. [PubMed]
104. Ho KK, Flood P. Single amino acid residue in the extracellular portion of transmembrane segment 2 in the nicotinic alpha7 acetylcholine receptor modulates sensitivity to ketamine. Anesthesiology. 2004;100:657–662. [PubMed]
105. Sasaki T, Andoh T, Watanabe I, et al. Nonstereoselective inhibition of neuronal nicotinic acetylcholine receptors by ketamine isomers. Anesth Analg. 2000;91:741–748. [PubMed]
106. Durieux ME. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesth Analg. 1995;81:57–62. [PubMed]
107. Morita T, Hitomi S, Saito S, et al. Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice. Psychopharmacology (Berl) 1995;117:396–402. [PubMed]
108. Kikuchi T, Wang Y, Shinbori H, et al. Effects of ketamine and pentobarbitone on acetylcholine release from the rat frontal cortex in vivo. Br J Anaesth. 1997;79:128–130. [PubMed]
109. Nelson CL, Burk JA, Bruno JP, et al. Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats. Psychopharmacology (Berl) 2002;161:168–179. [PubMed]
110. Mashour GA. Monitoring Consciousness: EEG-based measures of anesthetic depth. Seminars in Anesthesia, Perioperative Medicine and Pain. 2006;25:205–210.
111. Mandryk M, Fidecka S, Poleszak E, et al. Participation of adenosine system in the ketamine-induced motor activity in mice. Pharmacol Rep. 2005;57:55–60. [PubMed]
112. Eger EI., 2nd Isoflurane: a review. Anesthesiology. 1981;55:559–576. [PubMed]
113. Berger AJ, Bayliss DA, Viana F. Modulation of neonatal rat hypoglossal motoneuron excitability by serotonin. Neurosci Lett. 1992;143:164–168. [PubMed]
114. Brandes IF, Zuperku EJ, Stucke AG, et al. Isoflurane depresses the response of inspiratory hypoglossal motoneurons to serotonin in vivo. Anesthesiology. 2007;106:736–745. [PubMed]
115. Whittington RA, Virag L. Isoflurane decreases extracellular serotonin in the mouse hippocampus. Anesth Analg. 2006;103:92–98. [PubMed]
116. Georgiev SK, Wakai A, Kohno T, et al. Actions of norepinephrine and isoflurane on inhibitory synaptic transmission in adult rat spinal cord substantia gelatinosa neurons. Anesth Analg. 2006;102:124–128. [PubMed]
117. Kumar VM, Vetrivelan R, Mallick HN. Noradrenergic afferents and receptors in the medial preoptic area: neuroanatomical and neurochemical links between the regulation of sleep and body temperature. Neurochem Int. 2007;50:783–790. [PubMed]
118. Kushikata T, Hirota K, Kotani N, et al. Isoflurane increases norepinephrine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro: Relevance to thermoregulation during anesthesia. Neuroscience. 2005;131:79–86. [PubMed]
119. Passani MB, Giannoni P, Bucherelli C, et al. Histamine in the brain: beyond sleep and memory. Biochem Pharmacol. 2007;73:1113–1122. [PubMed]
120. Hashimoto Y, Hashimoto Y, Hirota K, et al. Inhibited hypothalamic histamine metabolism during isoflurane and sevoflurane anesthesia in rats. Acta Anaesthesiol Scand. 1998;42:858–863. [PubMed]
121. Gallopin T, Fort P, Eggermann E, et al. Identification of sleep-promoting neurons in vitro. Nature. 2000;404:992–995. [PubMed]
122. Isaac SO, Berridge CW. Wake-promoting actions of dopamine D1 and D2 receptor stimulation. J Pharmacol Exp Ther. 2003;307:386–394. [PubMed]
123. Adachi YU, Yamada S, Satomoto M, et al. Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum. Brain Res Bull. 2005;67:176–181. [PubMed]
124. Adachi YU, Yamada S, Satomoto M, et al. Isoflurane anesthesia inhibits clozapine- and risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: An in vivo microdialysis study. Neurochemistry international. 2008;52:384–391. [PubMed]
125. Keita H, Henzel-Rouelle D, Dupont H, et al. Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate-evoked dopamine release in rat striatal slices: evidence for direct presynaptic effects. Anesthesiology. 1999;91:1788–1797. [PubMed]
126. Wisor JP, Nishino S, Sora I, et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001;21:1787–1794. [PubMed]
127. Votaw J, Byas-Smith M, Hua J, et al. Interaction of isoflurane with the dopamine transporter. Anesthesiology. 2003;98:404–411. [PubMed]
128. Votaw JR, Byas-Smith MG, Voll R, et al. Isoflurane alters the amount of dopamine transporter expressed on the plasma membrane in humans. Anesthesiology. 2004;101:1128–1135. [PubMed]
129. Byas-Smith MG, Li J, Szlam F, et al. Isoflurane induces dopamine transporter trafficking into the cell cytoplasm. Synapse. 2004;53:68–73. [PubMed]
130. Bortone L, Ingelmo P, Grossi S, et al. Emergence agitation in preschool children: double-blind, randomized, controlled trial comparing sevoflurane and isoflurane anesthesia. Paediatr Anaesth. 2006;16:1138–1143. [PubMed]
131. Irifune M, Sato T, Nishikawa T, et al. Hyperlocomotion during recovery from isoflurane anesthesia is associated with increased dopamine turnover in the nucleus accumbens and striatum in mice. Anesthesiology. 1997;86:464–475. [PubMed]
132. Mashour GA, Forman SA, Campagna JA. Mechanisms of general anesthesia: from molecules to mind. Best Pract Res Clin Anaesthesiol. 2005;19:349–364. [PubMed]
133. Hapfelmeier G, Haseneder R, Eder M, et al. Isoflurane slows inactivation kinetics of rat recombinant alpha1beta2gamma2L GABA(A) receptors: enhancement of GABAergic transmission despite an open-channel block. Neurosci Lett. 2001;307:97–100. [PubMed]
134. Ming Z, Knapp DJ, Mueller RA, et al. Differential modulation of GABA- and NMDA-gated currents by ethanol and isoflurane in cultured rat cerebral cortical neurons. Brain Res. 2001;920:117–124. [PubMed]
135. Liachenko S, Tang P, Somogyi GT, et al. Concentration-dependent isoflurane effects on depolarization-evoked glutamate and GABA outflows from mouse brain slices. Br J Pharmacol. 1999;127:131–138. [PMC free article] [PubMed]
136. Gyulai FE, Mintun MA, Firestone LL. Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane. Anesthesiology. 2001;95:585–593. [PubMed]
137. Zhang Y, Wu S, Eger EI, 2nd, et al. Neither GABAA nor strychnine-sensitive glycine receptors are the sole mediators of MAC for isoflurane. Anesth Analg. 2001;92:123–127. [PubMed]
138. Nitz D, Siegel JM. GABA release in the locus coeruleus as a function of sleep/wake state. Neuroscience. 1997;78:795–801. [PubMed]
139. Nitz D, Siegel JM. GABA release in posterior hypothalamus across sleep-wake cycle. Am J Physiol. 1996;271:R1707–1712. [PubMed]
140. Dong HL, Fukuda S, Murata E, et al. Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat. Anesthesiology. 2006;104:122–133. [PubMed]
141. Vanini G, Watson CJ, Bouchard LA, et al. GABA levels in substania innominata (SI) of cat basal forebrain are state dependent. Sleep. 2007;30(Abstract Supplement):A3.
142. Freund TF, Gulyas AI. GABAergic interneurons containing calbindin D28K or somatostatin are major targets of GABAergic basal forebrain afferents in the rat neocortex. J Comp Neurol. 1991;314:187–199. [PubMed]
143. Freund TF, Meskenaite V. gamma-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc Natl Acad Sci USA. 1992;89:738–742. [PubMed]
144. Manns ID, Alonso A, Jones BE. Discharge profiles of juxtacellularly labeled and immunohistochemically identified GABAergic basal forebrain neurons recorded in association with the electroencephalogram in anesthetized rats. J Neurosci. 2000;20:9252–9263. [PubMed]
145. Borghese CM, Werner DF, Topf N, et al. An isoflurane- and alcohol-insensitive mutant GABAA receptor alpha(1) subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice. J Pharmacol Exp Ther. 2006;319:208–218. [PubMed]
146. Yamashita M, Ikemoto Y, Nielsen M, et al. Effects of isoflurane and hexafluorodiethyl ether on human recombinant GABAA receptors expressed in Sf9 cells. Eur J Pharmacol. 1999;378:223–231. [PubMed]
147. Neumahr S, Hapfelmeier G, Scheller M, et al. Dual action of isoflurane on the gamma-aminobutyric acid (GABA)-mediated currents through recombinant alpha(1)beta(2)gamma(2L)-GABAA-receptor channels. Anesth Analg. 2000;90:1184–1190. [PubMed]
148. Zhang Y, Stabernack C, Sonner J, et al. Both cerebral GABAA receptors and spinal GABAA receptors modulate the capacity of isoflurane to produce immobility. Anesth Analg. 2001;92:1585–1589. [PubMed]
149. Lambert S, Arras M, Vogt KE, et al. Isoflurane-induced surgical tolerance mediated only in part by beta3-containing GABAA receptors. Eur J Pharmacol. 2005;516:23–27. [PubMed]
150. Larsen M, Valo ET, Berg-Johnsen J, et al. Isoflurane reduces synaptic glutamate release without changing cytosolic free calcium in isolated nerve terminals. Eur J Anaesthesiol. 1998;15:224–229. [PubMed]
151. Winegar BD, MacIver MB. Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys. BMC Neurosci. 2006;7:5. [PMC free article] [PubMed]
152. Zuo Z. Isoflurane enhances glutamate uptake via glutamate transporters in rat glial cells. Neuroreport. 2001;12:1077–1080. [PubMed]
153. Cechova S, Zuo Z. Inhibition of glutamate transporters increases the minimum alveolar concentration for isoflurane in rats. Br J Anaesth. 2006;97:192–195. [PubMed]
154. Larsen M, Hegstad E, Berg-Johnsen J, et al. Isoflurane increases the uptake of glutamate in synaptosomes from rat cerebral cortex. Br J Anaesth. 1997;78:55–59. [PubMed]
155. Huang Y, Zuo Z. Isoflurane enhances the expression and activity of glutamate transporter type 3 in C6 glioma cells. Anesthesiology. 2003;99:1346–1353. [PubMed]
156. Huang Y, Feng X, Sando JJ, et al. Critical role of serine 465 in isoflurane-induced increase of cell-surface redistribution and activity of glutamate transporter type 3. J Biol Chem. 2006;281:38133–38138. [PubMed]
157. Dickinson R, Peterson B, Banks P, Simillis C. Competitive Inhibition at the Glycine Site of the N-Methyl-D-aspartate Receptor by the Anesthetics Xenon and Isoflurane. Anestheisology. 2007;107:756–767. [PubMed]
158. Violet JM, Downie DL, Nakisa RC, et al. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology. 1997;86:866–874. [PubMed]
159. Yamashita M, Mori T, Nagata K, et al. Isoflurane modulation of neuronal nicotinic acetylcholine receptors expressed in human embryonic kidney cells. Anesthesiology. 2005;102:76–84. [PubMed]
160. Flood P, Coates KM. Sensitivity of the alpha7 nicotinic acetylcholine receptor to isoflurane may depend on receptor inactivation. Anesth Analg. 2002;95:83–87. [PubMed]
161. Matsuura T, Kamiya Y, Itoh H, et al. Inhibitory effects of isoflurane and nonimmobilizing halogenated compounds on neuronal nicotinic acetylcholine receptors. Anesthesiology. 2002;97:1541–1549. [PubMed]
162. Nietgen GW, Honemann CW, Chan CK, et al. Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function. Br J Anaesth. 1998;81:569–577. [PubMed]
163. Do SH, Kamatchi GL, Durieux ME. The effects of isoflurane on native and chimeric muscarinic acetylcholine receptors: the role of protein kinase C. Anesth Analg. 2001;93:375–381. [PubMed]
164. Shichino T, Murakawa M, Adachi T, et al. Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum. Acta Anaesthesiol Scand. 1997;41:1335–1340. [PubMed]
165. Keifer JC, Baghdoyan HA, Lydic R. Pontine cholinergic mechanisms modulate the cortical electroencephalographic spindles of halothane anesthesia. Anesthesiology. 1996;84:945–954. [PubMed]
166. Jansson A, Olin K, Yoshitake T, et al. Effects of isoflurane on prefrontal acetylcholine release and hypothalamic Fos response in young adult and aged rats. Exp Neurol. 2004;190:535–543. [PubMed]
167. Segerdahl M, Ekblom A, Sandelin K, et al. Peroperative adenosine infusion reduces the requirements for isoflurane and postoperative analgesics. Anesth Analg. 1995;80:1145–1149. [PubMed]
168. Segerdahl M, Persson E, Ekblom A, et al. Peroperative adenosine infusion reduces isoflurane concentrations during general anesthesia for shoulder surgery. Acta Anaesthesiol Scand. 1996;40:792–797. [PubMed]
169. Boison D. Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol. 2008;8:2–7. [PMC free article] [PubMed]
170. Liu Y, Xiong L, Chen S, et al. Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists. Can J Anaesth. 2006;53:194–201. [PubMed]
171. Tas PW, Eisemann C, Roewer N. The volatile anesthetic isoflurane suppresses spontaneous calcium oscillations in vitro in rat hippocampal neurons by activation of adenosine A1 receptors. Neurosci Lett. 2003;338:229–232. [PubMed]
172. Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many questions, few answers. Anesth Analg. 2007;104:84–91. [PubMed]
173. Aghajanian GK, VanderMaelen CP. α2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science. 1982;215:1394–1396. [PubMed]
174. Yasui Y, Masaki E, Kato F. Sevoflurane directly excites locus coeruleus neurons of rats. Anesthesiology. 2007;107:992–1002. [PubMed]
175. Anzawa N, Kushikata T, Ohkawa H, et al. Increased noradrenaline release from rat preoptic area during and after sevoflurane and isoflurane anesthesia. Can J Anaesth. 2001;48:462–465. [PubMed]
176. Silva JH, Gomez RS, Diniz PH, et al. The effect of sevoflurane on the release of [3H]dopamine from rat brain cortical slices. Brain Res Bull. 2007;72:309–314. [PubMed]
177. Hapfelmeier G, Schneck H, Kochs E. Sevoflurane potentiates and blocks GABA-induced currents through recombinant alpha1beta2gamma2 GABAA receptors: implications for an enhanced GABAergic transmission. Eur J Anaesthesiol. 2001;18:377–383. [PubMed]
178. Kira T, Harata N, Sakata T, et al. Kinetics of sevoflurane action on GABA- and glycine-induced currents in acutely dissociated rat hippocampal neurons. Neuroscience. 1998;85:383–394. [PubMed]
179. Nishikawa K, Kubo K, Ishizeki J, et al. The interaction of noradrenaline with sevoflurane on GABA(A) receptor-mediated inhibitory postsynaptic currents in the rat hippocampus. Brain Res. 2005;1039:153–161. [PubMed]
180. Moe MC, Berg-Johnsen J, Larsen GA, et al. Sevoflurane reduces synaptic glutamate release in human synaptosomes. J Neurosurg Anesthesiol. 2002;14:180–186. [PubMed]
181. Vinje ML, Moe MC, Valo ET, et al. The effect of sevoflurane on glutamate release and uptake in rat cerebrocortical presynaptic terminals. Acta Anaesthesiol Scand. 2002;46:103–108. [PubMed]
182. Scheller M, Bufler J, Schneck H, et al. Isoflurane and sevoflurane interact with the nicotinic acetylcholine receptor channels in micromolar concentrations. Anesthesiology. 1997;86:118–127. [PubMed]
183. White NS, Alkire MT. Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness. Neuroimage. 2003;19:402–411. [PubMed]
184. Gallezot JD, Bottlaender M, Gregoire MC, et al. In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med. 2005;46:240–247. [PubMed]
185. Alkire MT, McReynolds JR, Hahn EL, et al. Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat. Anesthesiology. 2007;107:264–272. [PubMed]
186. Mashour GA. Integrating the science of consciousness and anesthesia. Anesth Analg. 2006;103:975–982. [PubMed]
187. Nofzinger EA. Neuroimaging of sleep and sleep disorders. Curr Neurol Neurosci Rep. 2006;6:149–155. [PubMed]
188. Tononi G. Consciousness, information integration, and the brain. Prog Brain Res. 2005;150:109–126. [PubMed]
189. Plum F, Posner JB. The diagnosis of stupor and coma. 3d. F. A. Davis Co.; Philadelphia: 1980.
190. Hobson JA. What is a Behavioral State? In: Ferrendelli JA, editor. Neuroscience Symposia: Aspects of Behavioral Neurobiology. Vol. 3 Bethesda, MD: 1978.
191. McGuire BE, Basten CJ, Ryan CJ, et al. Intensive care unit syndrome: a dangerous misnomer. Arch Intern Med. 2000;160:906–909. [PubMed]
192. Paton WD. How far do we understand the mechanism of anaesthesia? Eur J Anaesthesiol. 1984;1:93–103. [PubMed]
193. Mashour GA. Consciousness unbound: toward a paradigm of general anesthesia. Anesthesiology. 2004;100:428–433. [PubMed]