REM sleep pathways and anticholinesterase intoxication: A mechanism for nerve agent-induced, central respiratory failure

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Medical Hypotheses

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REM Sleep Pathways and Anticholinesterase Intoxication: A Mechanism for Nerve Agent-induced, Central Respiratory Failure A. KOK SAG

626 Towne Center Drive, Suite 201, Joppa, MD 21085, USA

Abstract-The mechanism of death following exposure to anticholinesterases, such as the highly toxic nerve agents soman and VX, and other organophosphate anticholinesterases such as the insecticide parathion, remains unclear, although evidence from nerve agent research suggests that death occurs by an atropine blockable respiratory failure mediated through mechanisms involving the central nervous system. It is proposed that REM sleep pathways, which can be triggered by acetylcholine accumulation in the pontomedullar reticular field, mediate respiratory failure through the inhibition of respiratory muscles. Cholinergic activation of REM sleep activities may also account for other physiological and behavioural effects that follow exposure to nerve agents. These include forebrain activation, which is associated with EEG desynchronization and seizures, locomotor depression with concomitant loss of righting reflex, and limb jerks and extensions. Pharmacologic evidence for atropine and clonidine protection against soman intoxication effects is entirely consistent with a scenario of cholinergic receptor activation in the pontomedullar reticular field.

Nerve agents such as VX, soman, and sarin are extremely potent inhibitors of the acetylcholine (ACh) transmitter-regulating enzyme, acetylcholinesterase (AChE). Laboratory rats exposed to low, but lethal doses of soman are likely to exhibit two major intoxication effects, seizures and respiratory failure, that appear separable with differential therapeutic intervention. Although some animals may die from airway secretions, others succumb to respiratory failure that appears to originate from CNS malfunction. This discussion focuses on a cholinergically regulated system that may cause respiratory failure following systemic nerve agent exposure. Unless otherwise stated, most

of the research described here derives from studies in the cat. There are two major cholinergic cell regions in the brain (Pig. la). In the lower forebrain lies the basal gangliar region, which sends wide-ranging projections to cortical cells and limbic structures. At the back of the midbrain, where it meets the pans, is the pontomesencephalic tegmental (PMT) region. Although both regions are likely to be fundamentally involved in the generation of seizures, only the rear site sends significant cholinergic projections to the hindbrain, where most respiratory control sites are found. The PMT region generally contains two cholinergic

Date received 6 July 1992 Date accepted 22 August 1992

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Fie. 1 a) General locations of fore and hindbrain cholinergic regions (stars). b) Diagramatic representation of shaded area in la showing hindbrain regions relevant to text discussion.

sites, one in the latemdotsal tegmentum and the other in the pedunculopontine nucleus. There is considerable overlap between these sites with respect to the brain regions to which they send choline@ projections, although specific targeting varies (l-4). Although the mechanism of anticholinesterase-induced central respiratory failure remains unclear, there is evidence to suggest that hypercholinergic stimulation mediated by the hindbrain cholinergic PMT center may figure prominently in the process. In this article, it is proposed that soman-induced respiratory failure, as well as locomotor depression, is mediated by or substantially contributed to by hindbrain cholinergic pathways that normally inhibit skeletal muscles during rapid eye movement (REM) sleep, or REM-associated muscle atonia. Soman-induced respiratory failure Regarding the effects of soman, this discussion focuses on work by Chang et al (5). who simultaneously characterized, in soman-injected, unanesthetized guinea pigs, two respiratory activities: 1) electrical activity of central respiratory drive cells in the ventral respiratory group of the medulla, and 2) diaphragm muscle response to that drive, as reflected by electromyogram (EMG) profiles. These data show activ-

ity traces during successive phases of soman-altered respiratory activity which subsequently results in respiratory failure (Fig. 2). The respiratory rate progressively decreases over time, due to increases in both the duration of inspiratory burst/contraction events and the interval between each event (compare Figs 2b and 2e). EMG characteristics also change. Under normal conditions and just after intoxication, EMG burst amplitude peaks early or at the middle of the burst. Subsequently, however, the EMG signal peaks sharply at the end of each inspiratory contraction. In addition, some EMG contractile episodes, referred to as fasciculations, show continued inspiratory firing (Fig. 2d, arrows), reflccting irregular muscle stimulation that persists, as indicated by the burst pattern of inspiratory drive cells, into what should be the expiratory phase. Respiratory drive cells continue to fire rhythmically, showing strong signaIs, albeit with some irregularities, close to the time when regular bursting rhythm stops (respiratory arrest). Furthermore, diaphragmatic contractile response to this drive persists throughout the period of respiratory decline and, as judged from occasional postapneic firing, even after respiratory arrest. Hence, between drive cell and diaphragm contractile response, no clear cause for the cessation of breathing is evident. Both the Chang

REM SLEEP PATHWAYS AND ANTICHOLINESTERASE INTOXICATION

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Chang et al (5) to suggest that respiratory failure is likely to result from a loss of coordinated contractile

timing between upper respiratory (laryngeal and/or phatyngeal) muscles and the diaphragm. REM sleep: Excitation to the front, inhibition to the back b

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Fig. 2 Panels from Chang et al (5) depicting progressive changes in medullar respiratory rhythm (top row of each panel), diaphragm EMG (middle rows), and integrated EMG (bottom rows).

study using guinea pigs exposed to soman and that of Foutz et al (6), using unanesthetized cats exposed to parathion show that central drive persists under conditions of lethal or maximal levels of AChE inhibition. This persistence of drive response, coupled with recurrent fasciculations during the expiratory phase, led

REM sleep is mediated by the activation of PMT cholinergic outputs extending to mid- and forebrain sites and downward to the hindbrain (4). During this sleep state, PMT cholinergic output to midbrain thalamic nuclei, and possibly also to the forebrain cholinergic cell region, induces a state of general cortical activation. This activation is associated with cortical electroencephalographic (EEG) desyncrhonization, which, along with skeletal muscle atonia, is a defining characteristic of the REM sleep state. REM sleep is punctuated with periods of rapid eye movement, a phenomenon thought to correspond with visual orientation behaviour during active dreaming. The frequent episodes of rapid eye movement during REM sleep are coupled with pontogeniculooccipital brain waves (PGO waves) to define the phasic component of REM sleep. REM sleep is often referred to as paradoxical sleep since, while the forebrain becomes highly active, the activities of postural and other skeletal muscles are maintained in an inhib ited state because of descending cholinergic fibers (7). Presumably, this muscle atonia prevents acting out in response to dreaming (8,9). Also, during phasic REM sleep, short bursts of myoclonic activity in the form of twitches and jerks are seen most frequently in the hindlimbs (10, 11). Recordings made across the sleepwakefulness cycle of diaphragm EMGs or of activity of the phrenic nerve, which innervates the diaphragm (12,13), show distinctive changes during REM sleep, particularly with respect to phasic periods of REM sleep. During these episodes, EMG recordings show an increased number of irregular contraction events, and changes in the amplitude profiles of inspiratory burst events. The latter include bursts showing increasing amplitude with each contraction. This burst profile superficially resembles that seen by Chang et al (5). although with a lower rise in the slope, and was interpreted as reflecting an inhibition of inspiration (12). EMG recordings made during REM sleep also show characteristic irregularities, called fractionations, that, with respect to timing, resemble some of the fasciculations described by Chang et al (5). REM sleep fmctionations are stuttering bursts of diaphragmatic inspiratory activity that extend into the expiratory phase (13, 14). Finally, some phrenic motor units were found to cease activity altogether during REM (15).

144 REM and soman: The connections That REM pathways may be activated during systemic soman intoxication is suggested by the presence of similar phenomena or consistencies: a) Both soman intoxication and REM sleep induction are fundamentally cholinergic phenomena (4, 16-22). b) Both REM sleep and the initial phase of agent intoxication are characterized by EEG desynchronization (4). c) REM pathways contribute strongly to cortical and general forebrain activation (4), a likely prelude to the generation of agent-induced seizures. d) Both soman and descending REM pathways may cause an atropine-blockable respiratory depression, as described in this article (21). e) Descending muscle atonia/hypotonia pathways can explain soman-induced loss of righting reflex and locomotor depression (23, 24). I) Myoclonic episodes that interrupt the REM atonic state may represent behavioral parallels to agent-induced limb jerks and extensions. g) Changes in respiratory cycle time and some REM-associated diaphragmatic EMG or diaphragmatic (phrenic) nerve activities (5, 12, 13) bear at least a superficial resemblance to soman-induced activity profiles. Most of the parallels regarding REM- and somaninduced motor effects, such as postural muscle inhibition, are relatively straightforward. Respiratory failure via REM motor inhibition, however, requires some explaining since Chang et al (5) found that medullar drive activity is able to cause diaphragm contraction, even after respiratory failure. In the remaining discussion, respiratory depression will first be described as it may be elicited by pathways likely to be active during REM sleep. Following this, these pathways will be examined with respect to their potential roles in the mediation of respiratory failure induced by soman or other anticholinesterases. REM sleep-associated muscle inhibition and respiratory depression Various studies suggest that REM sleep is initiated by the activity of cholinergic cells in the PMT cholinergic region (25). These cells send their axons to cholinoceptive (ACh-responding) cells bilaterally located in the pontine and medullar reticular fields (26) (Fig. lb). Kawahara and Suzuki (27) showed that many of the latter project, via a second of group cells in the medulla, down the spinal cord, presumably to motoneuron sites (28, 29, 30). REM motor inhibition

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has been variously described to be direct or indirect for brainstem or spinal motoneurons (11,3 1,32). The path of diaphragmatic inhibitory fibers is unknown, although anatomical studies have shown the existence of reticulospinal fibers projecting to the phrenic motoneuron site (33). Injection of carbachol, a nonmetabolizable cholinergic agonist, into the medial pontine reticular field (PRF) in vivo shows that the majority of cholinoceptive cells there become excited (17, 18). In response to carbachol, these cells initiate a general REM-type sleep state, as evidenced by the induction of forebrain activation, EEG desynchronization, PGO waves, and muscle atonia. Microdialysis studies by Lydic et al (20) show a clear dose dependence between carbachol injection and REM sleep induction. Although diaphragm muscle inhibition can be induced concurrently with postural muscle atonia, it has only been shown to be substantial or complete in decerebrate animals (e.g. those with tbalamic pathway transections (21)). This suggests that some uncharacterized fore- or midbrain pathway activity normally (and selectively) prevents diaphragm muscle inhibition during REM sleep. Respiratory atonia/hypotonia in the decerebrate cat has been studied by two groups using carbachol injection or electrical stimulation into the pontine reticular field PRF (21,27, 34, 35, 36). Electrical stimulation induced a complete, rather than partial suppression of phrenic nerve activity, probably because electrical stimulation can be expected to excite both local cells and fibers passing through the stimulus region. Carbachol depression of respiratory motor nerve activities was found to be considerable in these animals; activity of the phrenic nerve fell to about 65% of its control value, inspiratory intercostal activity fell to about 50%. and hypoglossal and expiratory intercostal motor nerve activities fell profoundly to about 10% and 5% of their normal values. The phrenic, intercostal and hypoglossal nerves carry motoneuron fibers that control diaphragmatic contmction, ribcage contraction, and upper respiratory tract (tongue) muscle contraction, respectively. Respiratory rate decreased by 30% (Fig. 3). Intact, carbachol-injetted cats also showed a large decrease in respiratory frequency compared to those seen in awake animals and animals in natural REM sleep (21). As suggested from studies of REM sleep in intact animals (37), carbachol injection into the PRF of decerebrate cats showed that upper airway and diaphragm respiratory muscles are differentially affected. However, Kawahara’s traces show that even in the decerebmte animals, diaphragmatic atonia is shortlived despite continued electrical stimulation of the

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Fig. 3 Data from Kimura et al (21) showing effects of PRP-injected carbachol(O.11 pg) and atropine (0.16 pg) on nerve activities. Left panel (control); middle panel (carbachol); right panel (carbachol followed by atropine). PHR; phrenic nerve: IC, intercostal nerve; HYPE, hypoglossal nerve: C4; a motor branch of the C4 nerve (nonrespiratory).

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DTF Fig. 4 Tracing from Kawahara et al (34) showing effect of etectrical stimulation of PRF. Diaphragm EMG (top), integrated Eh4G (middle) and pC02 (bottom) are shown. Duration of stimulus is about 2 min.

PRF region (in contrast, motoneural output to a leg muscle, to the external intercostal muscles, and through the hypoglossal nerve, remained suppressed (35, 36)). Inhibition was interrupted by strong hyperventilating inhalations @CO2 falling below prestimulation control values) that persisted until stimulation ended. At the end of stimulation, the original drive bursting pattern immediately returned with increased vigor before assuming the prestimulus control rhythm (Fig. 4; note integrated EMG). The latter observation suggests that REM-type suppression of normal diaphragm output continues unheeded throughout the stimulation period, and that the rebound effect could represent a combination of two drive inputs. Further

experimental manipulation of respiratory function to achieve different levels of pCB2 indicated that the presence and duration of diaphragm inhibition depends on pC02 levels. Hence, the strong hyperventilating response may originate from central chemoresponsive components (high pC02 or low p02 response centers (36)). REM muscle inhibition and soman-induced respiratory failure

Could REM muscle inhibition pathways be responsible for soman-induced locomotor effects and respiratory failure? Considering the evidence, activation of these pathways following AChE inhibition seems a very likely possibility. At the behavioral level, the loss of righting reflex, the locomotor depression, and, possibly, the myoclonic actions seen in soman-exposed animals (24) are consistent with some measure of REM-type muscle atonia. At the neurophysiological level, several observations suggest that activation of the REM atonia pathway at the PMT is not unlikely under conditions of soman poisoning. Microinjection of neostigmine, an AChE inhibitor, into the PRF promotes REM-type sleep in a dose dependent manner (38). Intravenous administration of physostigmine, a similar compound, may induce an atropine-blockable episodes of REM sleep signs, including muscle atonia (39). Studies by Lydic et al (20) hint that carbachol stimulation of cells on one side of the PRF results in ACh release on the other side, possibly via reciprocal connections with the PMT region. This observation suggests that under conditions of AChE inactivation, some level of self-reinforcement of ACh release into the PRF could take place. Furthermore, cholinergic hyperstimulation of the norepinephrine-producing locus ceruleus (a site adjacent to the PMT), presumably by PMT cholinergic cells, may occur soon after soman exposure, as judged from c-fos expression there (40). The elimination of regulatory norepinephrine output from the locus ceruleus might result in REM pathway activation in the presence of AChE inhibitors (25, 41, 42, 43). These observations, at least, are suggestive of conditions wherein acetylcholine accumulation in the PRF can be promoted by self-reinforcement and/or loss of regulatory suppression by norepinephrine. The progressively decreasing respiratory frequency following soman intoxication may be evidence for the accumulation of acetylcholine in the PRF over time. Carbachol injection into that region in both decerebrate and intact cats results in large decreases in respiratory frequency. In all cases, both inspiratory burst length and interburst interval contribute to the cycling time increase (5, 21).

146 How REM sleep atonia/hypotonia of muscles in the respiratory system may lead to apnea is unclear, since more than one scenario is possible. Respiratory failure could derive from depression of diaphragm muscles, muscles of the upper respiratory tract (in the larynx or pharynx), or a combination of the two. Possible mechanisms leading to respiratory failure and apnea are discussed below. Failure of diaphragmatic function As noted above, strong diaphragm motor depression appears to require decerebration, or the effective loss of some pathway that protects this muscle from atonia/hypotonia How might this condition be met? Following soman intoxication, the function of such a descending forebrain pathway could be disrupted by seizures. Alternatively, drugs such as diazepam or MK801, which can block seizures but do not protect against death, could effect similar pathway disruption since they act on very commonly found receptors. Furthermore, if diaphragmatic failure alone is to explain apnea, a second failure must occurs that of Kawahara’s hyperventilatory pathway. The possible presence of two diaphragmatic stimulatory inputs, one suppressible by atonia pathways while the other remains unaffected, is consistent with the contention by Lumsden and others (see (45)) that there are two inspiratory drives. These are the normal, or eupneic inspiratory drive, and the gasping drive, which takes over under conditions of hypoxia (low p02) or hypercapnea (high pC02). Normal eupneic drive, as reflected by traces of diaphragm EMG or phrenic nerve activity, shows motoneuron pool bursts to possess a mildly sloping amplitude profile with a peak generally located at the center. Gasping differs in that motor cells and, by extension, muscle cells, are activated in a tight, higher amplitude burst with little or no sloping which results in a fast and deep inhalation contraction (45). Richardson (46) showed that the eupneic and gasping bursts of the phrenic nerve differ in frequency (80 vs 120 Hz, respectively). In light of the two-drive model, it is possible that the failure of the persistently responsive respiratory drive recorded by Chang et al (5) represents the decline of the gasping pathway after eupneic drive suppression. This interpretation is consistent with the persistence of coupled medullar drive bursting and diaphragmatic contraction in that study; the rather sharp rise in EMG inspimtory contraction profiles may reflect an apparent transition from eupneic to gasping drives across individual phrenic nerve bursts that has been documented and characterized by Richardson (46). This interpretation would lead to the prediction

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that eupneic drive is either lost or overridden by gasping when the rising burst profile is no longer evident. Although the activation of both ascending and descending REM pathways is likely to follow lethal soman exposures, other cholinergic pathways may have contributed to the respiratory depression described. Although Kimura et al (21) showed that cholinergic fiber stimulation leads to respiratory depression, the electrical stimulation by Kawahara’sgroup can be expected to stimulate noncholinergic fibers as well. If a failure of gasping occurs (see below), the mechanism is unclear and may involve other cholinergic hindbrain components. More specifically, the response site for hypercapnea (high blood C02) in the ventral medulla is associated with cholinergic receptor activity (47, 48, 49). The nucleus ambiguus, associated with ventral respiratory drive function, also contains some intrinsic cholinergic cells (50), and the adjacent ventrolateral medulla receives a cholinergic projection from the pedunculopontine nucleus (51). REM-mediated loss of upper airway patency As noted above, diaphragm-mediated effects, such as a loss of eupneic drive, may combine with changes in upper airway muscles to cause respiratory failure. Muscles in the larynx, or voice box, in the pharynx at the back of the throat, and in the tongue are critical for the maintenance of an open upper respiratory tract during inspiration (5,52). Muscles such as the posterior cricoarytenoids, for example, open the larynx during inspiration, and are important to respiratory tract patency of animals such as rats or cats. Among animals, humans are particularly prone to oropharyngeal collapse involving muscles of the tongue and back of the throat. Also important are postural muscles of the neck that help hold the pharynx straight. Medical evidence (53, 54) and data obtained using intact (32, 37, 54) and decerebrate (21) animals variously suggest that laryngeal, tongue, and neck muscles are strongly depressed during REM sleep or after carbachol injection into the PRF. During normal REM sleep, the decrease in upper airway resistance that normally accompanies inspiration is diminished and intermittently absent (37). When this decrease is combined with other factors such as narrow pharyngeal passage diameter or strong inspiratory draw, apnea may result (52). This may occur in REM sleep apnea patients, who awaken in response to apnea. Awakening immediately restores active muscle tone in the respiratory tract, but represents a response that may be unavailable to victims of anticholinesterase intoxication in whom REM pathways remain activated. Under conditions of normal REM sleep in ap nea patients, upper airway hypotonia alone is un-

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likely to cause apnea. Considering the requirements for oropharyngeal collapse (52), one reasonable, although speculative scenario is that actions regarding both the diaphragm and the upper respiratory muscles combine to cause respiratory failure. Either by the failure of eupneic drive as described, or by hypercapnea and/or hypoxia (low blood p02) due to metabolic demand, or by inspiratory resistance caused by abnormally strong, ACh-induced upper airway muscle inhibition (54), the gasping response is elicited. Gasping then provides the necessary draw or negative pressure to collapse an upper airway with hypotonic musculature. This collapse would only serve to strengthen diaphragmic gasping, sealing the animal’s fate. Probably due to strong, negative intratboracic pressure from gasping, a secondary complication to this scenario can be pulmonary edema, which has been observed, in otherwise healthy patients, to immediately follow upper airway obstruction. With complete obstruction, this response is both swift and severe (S-58). Applicability to human organophosphorus pesticide exposures It is notable that some reports of severe pesticide anticholinesterase intoxication in man describe symptoms consistent with conditions of general or pharyngeal muscle flacidity (59, 60). Although intoxication effects mediated through REM sleep activation may be central to initial, acute intoxication events, its relevance to the subseqient muscle depression seen following insecticide exposure is unclear. Intermediate and longterm delayed sequelae may involve secondary, peripheral neuromuscular changes (61). Implications for medical intervention The mecahnism of nerve agent or anticholinesterase induced respiratory failure proposed here is entirely consistent with AChE inactivation being the primary cause of respiratory arrest and with muscarinic receptor blockade being able to block that arrest. Although respiratory failure, as well as convulsions, can be completely blocked by the timely application of drugs such as atropine or scopolamine (62) the use of adjuncts to diminish the REM pathway directed and PMT-mediated cholinergic contribution to forebrain seizures is conceivable under conditions where pretreatment or early treatment are possible. lXvo sets of transmitter receptor-interacting drugs might be effective as adjuncts: alpha2adrenergic agonists and histamine Hl receptor antagonists. The former have shown efficacy in the therapeutic intervention of narcolepsy in patients that fall rapidly into REM sleep (63). Alpha2-adrenergic agonists such as clonidine

have been shown to protect against soman-induced intoxication symptoms and death (23). Hl receptor blockade may prevent increased PMT cholinergic cell activation that may accompany stress (64), a condition likely relevant to laboratory animals as well as to military personnel in the field. Although serotonin uptake blockers have shown some efficacy in the narcoleptic dog model (64), recent findings regarding serotonin effects on the PMT region (66,67) suggest that it may act indirectly by enhancing NE release there; an effect that, as noted above, already appears to occur to the point of NE depletion with hypercholinergic stimulation of the locus ceruleus (41). Finally, prompt tracheal intubation can prevent upper airway collapse and could be lifesaving in the absence of effective diaphragm failure. References 1. Woolf N J. Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol 1991; 37: 475-524. 2. Woolf N J. Butcher L L. Cholinergic systems in the rat brain: III. Projections from the pontanesencephalic tegmmtum to the thalamus, tectum. basal ganglia, and basal forebrain. Brain Res Bull 1986; 16: 603-637. 3. Jones B E. Immunohistochemical study of choline acetyltransferase-immunoreactive processes and cells innervating the pontomedullary reticular formation in the rat. J Comp Neurol 1990, 295: 485-514. 4. Steriade M, McCarley R W. Brainstem Control of Wakefulness and Sleep. New York: Plenum Press, 1990. 5. Chang F-CT, Foster R E, Beers E T, Ricket D L, Filbert M G. Neurophysiological concomitants of soman-induced respiratory depression in awake, behaving guinea pigs. Toxic01 Appl Pbarmacol 1990. 102: 233-250. 6. Foutx A S. Delamanche I S, Denavit-SaubiC M. Persistence of central respiratory rhythmogenesis after maximal acetylcholinesterase inhibition in unanaesthetized cats. Can J Physiol Phamtacol 1989; 67: 162-166. I. Jouvet M, Michel F, Courjon J. Sur un stade’activitt Qectrique c&brale rap& au cours du sommeil physiologique. CR Sot Biol 1959; 153: 1024-1028. 8. Jouvet M. What does a cat dream about? Trends Neurosci 1979; 2; 15-16. 9. Schmck C H, Bundlie S R. Ettinger M G, Mahowald M W. Chronic behavioural disorders of human REM sleep: A new category of parasomnia. Sleep 1986; 9: 293-308. 10. Pompeiano 0. ‘Ihe Generation of Rhythmic Discharges During Bursts of REM. In: Chalazonitis M, Boisson M, eds. Abnormal Neuronal Discharges. New York: Raven Press, 1978. 11. Chase M H. Morales F R. The atonia and myoclcnia of active (REM) sleep. Ann Rev Psycho1 1999 41; 557-584. 12. Kline L R. Hendricks J C. Davies R 0. Pack A I. Control of activity .of the diaphragm in rapid-eye-movement sleep. J Appl Physid 1986; 61(4): 1293-1300. 13. Hendricks J C. Kline L R. Davies R 0, Pack A I. Effect of dorsolateral pontine lesions on diaphragmatic activity during REMS. J Awl Phvsiol 1990: 68(4): 1435-1442. 14. Orem J. Ne~ronal~mechanisms of ‘respiration in REM sleep. Sleep 1980, 3(3-4):251-267. 15. Sieck G C, Trelease R B. Harper R M. Sleep influences on diaphragmatic motor unit discharge. Exp Neural 1984; 85; 3 16-335.

148 16. Baghdoyan H A, Lydic R, Callaway C W, Hobson J A. The carbachol-induced e&ancement of desynchronized sleep signs is dose dependent and antagonized by centrally administered atropine. Neuropsychopharmacology 1989; 2(l): 67-70. 17. Greene R W, Gerber U, McCarley R W. Cholinergic activation of medial pontine reticular formation neurons in vitro. Brain Res 1989; 476: 154-159. 18. Greene R W. Haas H L, Gerber U, McCarley R W. Cholinetgic Activation of Medial Pontine Reticular Formation Neurons in vitro. In: Frctscher M. Misgeld U, eds. Central Cholinergic Synaptic Transmission. Basel: Birkhauser Verlag, 1989. 19. Lydic R, Baghdoyan H A. Wertz R, White D P. Cholinergic reticular mechanisms influence state-dependent ventilatoty response to hypercapnia Am J Physioll991; 261: R738-R746. 20. Lydic R, Baghdoyan H A. Lorinc 2. Microdialysis of cat pons reveals enhanced acetylcholine release during statedependent respiratory depression. Am J Physiol 1991; 261: R766-R770. 21. Kimura H, Kubin L. Davies R 0. Pack A I. Cholinergic stimulation of the pats depresses respiration in decerebrate cats. J Appl Physiol 1999 69(6): 2280-2289. J, Shalauta M D, Gillin J C. Shircmani 22. Velazquez-Moctezuma P J. Differential effects of cholinergic antagonists on REM sleep ccmpcnents. Psycbopharmacol Bull 1990; 26(3): 349. 23. Buccafusco J J, Aronstam R S. Clonidine protection from the toxicity of soman, and organophosphate acetylcbolinesterase inhibitor, in the mouse. J Pharmacol Exp ‘lher 1986; 239(l): 43. in24. Buccafusco J J. Protection against acetylcholinesterase hibitor toxicity by alpha-adrmergic agonists: A toxicological and neurochemical study. U.S. Army Medical Research and Development Command, Fort De&k, Frederick. Maryland, Contract No. DAMDl7-84-C-tll7. Annual Renott. 1987. sub25. Jones B E. Paradoxical sleep and its chemical/s&c&l strates in the brain. Neuroscience 1991: 40(3):637-656. 26. Grofova I, Keane S. Descending brainstem projections of the pedunculopontine tegmental nucleus in the rat. Anat Embryo1 1991; 184; 275-290. 21. Kawahara K. Suzuki M. Descending inhibitory pathway responsible for simultaneous suppression of postural tone and respiration in decembrate cats. Brain Res 1991; 538: 303-309. 28. Wu M-F, Siegel J M, Shouse M N, Schenkel E. Lesions producing REM sleep without atonia disinhibit the acoustic stattle reflex without affecting prepulse inhibition. Brain Res 1999 528: 330-333. 29. Rye D B, Lee H J, Saper C B, Wainer B H. Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J Comp Neurol 1988; 269: 315-341. 30. Mitani A, ho K, Mitani Y, McCarley R W. Descending projections from the gigantocellular tegmental field in the cat: Cells of origin and their brainstem and spinal cord trajectories. J Comp Nemo1 1988; 268: 546-566. 31. Chase M H, Chandler S H, Nakamura Y. Intracellular determination of membrane potential of trigeminal motoneurons during sleep and wakefulness. J Neurophysioll980,44: 349-358. 32. Glenn L L, Dement W C. Motoneuron properties during electromyogram pauses in sleep. Brain Res 1982, 243: 1 l-23. 33. Ellenberger H H, Vera P L, Haselton J R, Haseltcn C L. Schneidennan N. Brainstem projections to the phrenic nucleus: An anterograde and retrograde HRP study in the rabbit. Brain Res Bull 1990,24; 163-174. K, Nakazcoo Y, Kumagai S, Yamauchi Y, 34. Kawahara Miyamoto Y. Parallel suppression of extensor muscle tone and respiration by stimulation of pontine dorsal tegmentum in decerebrate cat. Brain Res 1988; 473; 81-90. K, Nakazono Y, Kumagai S. Yamauchi Y, 3.5. Kawahara

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