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Motion sickness may be caused by a neurohumoral action of acetylcholine
Medical Hypotheses 73 (2009) 790–793
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Motion sickness may be caused by a neurohumoral action of acetylcholine Leonard M. Eisenman * Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19038, USA
a r t i c l e
i n f o
Article history: Received 15 April 2009 Accepted 17 April 2009
s u m m a r y The mechanism by which motion stimulation results in the autonomic responses, known as motion sickness, has remained somewhat of an enigma. Neural connections between the vestibular nuclei and the autonomic and emetic centers in the brainstem have been described, but these appear to be relatively sparse. Thus, new or additional mechanisms seem warranted to account for this curious relationship. A new hypothesis is herein presented which posits that acetylcholine (ACh) acts as a neurohumeral agent to bring about the symptoms associated with motion sickness. Motion stimulation will activate primary vestibular afferents leading to activation of secondary vestibulocerebellar fibers, some of which are cholinergic, projecting to the vestibulocerebellar region of the posterior cerebellum. The acetylcholine, once released from these synaptic terminals diffuses into the CSF in the 4th ventricle. From there it gains access to the autonomic and emetic centers within the dorsal brainstem and can activate the cholinergic receptors in these nuclei to produce the symptoms characteristic of motion sickness. In similar fashion ACh would have access to the vestibular nuclei where it will facilitate transmission in these nuclei further reinforcing the vestibulocerebellar activity. This would serve as a positive feedback loop which will result in additional release of ACh from the cerebellum and further activation of the brainstem nuclei that result in the symptoms of motion sickness. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction The mechanism by which motion stimulation resulting from sea, train, air travel, etc., results in the visceral discomfort, commonly know as ‘‘motion sickness”, has remained an enigma. It is still not entirely clear how motion stimulation activates the visceral centers in the brainstem to produce the behavioral and autonomic responses, including ‘‘stomach awareness”, nausea, cold sweating, peri-oral and facial pallor, feeling of body warmth, dizziness, retching and recurrent vomiting experienced during motion sickness. As an explanation for these phenomena it might be surmised that there are extensive connections between the vestibular system and the autonomic and emetic centers in the brainstem. While there is some evidence for this anatomical linkage, it appears to be fairly limited [1–7]. Therefore, it seems reasonable to seek additional or other mechanisms by which the curious linkage between vestibular stimulation and motion sickness might arise. It is not intuitively obvious why such a linkage should exist at all. Emesis understandably results from the body’s attempt to eliminate ingested toxins. Why emesis should be linked to a motion induced conflict between sensory inputs is unclear. One evolutionary hypothesis suggests it may be an accidental by-product of ‘‘sensory conflict” [8]. This theory of motion sickness suggests that conflicting sensory inputs are necessary for motion sickness to develop [9– * Tel.: +1 215 593 7317; fax: +1 215 923 3808. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.04.031
11]. The evolutionary explanation as to why vestibular stimulation would result in such a debilitating condition, namely motion sickness, remains an open question. In this paper an alternative explanation is offered in the hope that it will be of heuristic value and stimulate further experimentation to determine its validity. The hypothesis is based on the premise that motion sickness is an accidental result of the anatomical relationships between the cerebellum, ventricular system and the dorsal brainstem. It encompasses the idea of a neurohumoral linkage, rather than direct synaptic connections between vestibular inputs and the visceral motor outputs [12]. In the present paper this concept is revisited and revised to incorporate acetylcholine (ACh) as the neurohumoral agent. Whereas previous work has suggested neural areas surrounding the 3rd ventricle as the site from which the suspected neurohumoral substance is released, the present hypothesis suggests the vestibulocerebellum as the proposed site from which the neurohumoral agent, ACh is released. In the following discussion the hypothesis will be presented first and then selected pertinent data will be reviewed in the light of this new mechanism for motion sickness. The hypothesis The hypothesis described below is summarized in Fig. 1. The peripheral vestibular apparatus, including the semicircular canals and the otolithic organs (utricle and saccule) provide an abundant input to the vestibular nuclei, located in the dorsal medullary
L.M. Eisenman / Medical Hypotheses 73 (2009) 790–793
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[19,17,20]. This would establish a positive feedback loop further activating the vestibulocerebellar afferents to the vestibulocerebellum resulting in additional release of ACh into the CSF. The positive feedback would potentiate the ACh effects on the neurons in the dorsal brainstem visceral nuclei and thus exacerbate motion sickness symptoms. This positive feedback loop might also account for the residual effects of motion sickness still present after the vestibular stimulation is no longer present, e.g. when someone experiencing motion sickness due to sea travel continues to feel queasy and uncomfortable when once again on dry land. Does it fit with existing data?
Fig. 1. This is a diagrammatic representation of the hypothetical framework for the generation of motion sickness symptoms as a result of motion stimulation. The labyrinth sends primary vestibular afferents to the vestibular nuclei (block arrow) and the vestibulocerebellum (thin black arrow). The presumed neurotransmitter in this pathway is glutamate (block arrow). The vestibular nuclei project to the autonomic nuclei in the dorsal brainstem (thin clear block arrow) and also to vestibulocerebellum via axonal projections and part of this pathway is cholinergic (curved arrow – ACh). The ACh released in the vestibulocerebellum diffuses (light gray block arrows – ACh) into the CSF of the 4th ventricle (IVth ventricle). ACh then diffuses (light gray block arrows-ACh) into the neurophil of the dorsal brainstem where there are nicotinic and/or muscarinic cholinergic receptors within the area postrema (AP) and the autonomic nuclei (e.g. NTS, DMX and ECRF). In addition, ACh diffuses into the vestibular nuclei in the dorsal brainstem where it interacts with cholinergic receptors to fascilitate the transmission of afferent input to the vestibulocerebellum. In this latter action it provides a positive feedback to enhance the further release of ACh from the vestibulocerebellar fibers. The end result is the activation of the autonomic and emetic nuclei and the genesis of motion sickness symptoms (sad face).
brainstem and also to the ventral regions of the posterior cerebellum, known as the vestibulocerebellum. In addition to these primary afferents there is also a robust projection from the vestibular nuclei to this same region of the cerebellum. This latter secondary projection system uses acetylcholine as one of its neurotransmitters [13,7]. It is highly probable that vigorous motion-induced vestibular stimulation would result in significant release of ACh from secondary vestibulocerebellar cholinergic mossy fiber afferents to the vestibulocerebellum. In many mammals and primates, including the human, the vestibulocerebellum is positioned directly over the 4th ventricle, which is situated between cerebellum and the brainstem. In particular, nuclei involved in autonomic regulation are situated within the dorsal portion of the brainstem immediately below the 4th ventricle. These nuclei include the nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMX), emetic centers located in the reticular formation (EMRF) and also the area postrema (AP), a circumventricular organ that is known to be a chemoreceptor trigger zone for emesis [14– 16]. The present hypothesis suggests that ACh released by the vestibulocerebellar afferents acts not only synaptically, to affect it’s postsynaptic targets, the granule cells in the vestibulocerebellar region, but that under the influence of vigorous vestibular stimulation sufficient ACh is released and diffuses into the underlying CSF in the 4th ventricle. Once in the 4th ventricle ACh would have access to neurophil in the dorsal brainstem and the autonomic nuclei where it could bind with cholinergic receptors found on many of the neurons in these visceral nuclei [17,18]. The neurohumoral activation of both synaptic and potentially extrasynaptic, ACh receptors would then mediate autonomic responses associated with motion sickness. In addition, ACh could also bind to cholinergic receptors found on the neurons within the vestibular nuclei
It is well known that an intact vestibular system is essential for the generation of motion sickness [9,21,22]. Thus, activation of vestibular afferents is necessary, but how does this input then activate the autonomic nuclei (NTS, DMX, EMRF, AP etc.) in the dorsal medullary brainstem that form an integral part of the emetic circuitry [23,19,24]? These autonomic and emetic areas are in close proximity to the vestibular nuclei, especially the medial and inferior vestibular nuclei. The most reasonable conclusion would be that there are neuroanatomical connections between the vestibular system and the visceromotor nuclei in the brainstem that account for the effects of vestibular stimulation on the generation of autonomic symptoms associated with motion sickness. However, while there is neuroanatomical and electrophysiological evidence that such linkages exist, these studies suggest that the connections are surprisingly sparse especially given the robust and long duration of the motion sickness response [1,2,4–6]. This raises the question as to whether vigorous motion stimulation might result in the activation of a different mechanism by which such stimulation affects dorsal brainstem structures responsible for the autonomic responses associated with motion sickness. Cerebellar involvement Primary vestibular afferents project to the vestibular nuclei and cerebellum. These primary vestibular afferents appear to use glutamate as their neurotransmitter [25]. Second order fibers from the vestibular nuclei project to the spinal cord, cerebellum, oculomotor centers and thalamus. With regard to the cerebellar target, it has been demonstrated that some of these projections are cholinergic [13,26]. Although the suggestion has been made that the vestibulocerebellar region is necessary for the elicitation of vomiting and other symptoms related to motion sickness, these data are inconsistent [27,28]. It is quite clear however, that this vestibulocerebellar region receives abundant input from the vestibular system [29]. Anatomically, the vestibulocerebellar region forms part of the roof over the posterior aspect of the IVth ventricle, which is situated between the cerebellum and the dorsal brainstem. Vestibular stimulation would therefore result in the activation of cholinergic synapses within the vestibulocerebellum. The released ACh could bind with receptors on postsynaptic granule and unipolar brush cells within the vestibulocerebellar region and then be degraded by cholinesterases. In addition to this however, it is proposed that certain types of vigorous motion-induced vestibular stimulation would result in significant release of ACh from these presynaptic terminals permitting its diffusion into the CSF. Once in the CSF high levels of ACh would be rapidly hydrolyzed by acetylcholinesterase before it could reach the dorsal brainstem. However, it appears that high concentrations of ACh inhibit acetylcholinesterase [30]. Thus, sufficient ACh may remain and allow to function in a neurohumoral fashion. If this were the case then ACh could have access to neurons in the dorsal brainstem that possess both synaptic and
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L.M. Eisenman / Medical Hypotheses 73 (2009) 790–793
possibly extrasynaptic cholinergic receptors. There is evidence to suggest that neurotransmitters are found within the CSF and that substances can diffuse into the brain parenchyma from the CSF {44} once in the neurophil both synaptic and extrasynaptic receptors can serve as binding sites for neurotransmitters [31–33]. There is also abundant evidence that neurons in the dorsal brainstem autonomic nuclei mentioned above express both nicotinic and muscarinic cholinergic receptors [34,17–19,25]. Thus, direct neurohumoral activation of the autonomic nuclei involved in motion sickness by ACh released from the cerebellum is feasible. It has also been shown that the transmission between first and second order vestibular neurons is facilitated by cholinergic agonists and disfacilitated by cholinergic antagonists [35]. In agreement with the above observations is the finding that scopolamine, a competitive inhibitor of muscarinic cholinergic receptors, is the most effective drug for the prevention of motion sickness [10,36]. Scopolomine’s site of action is still unclear but it likely involves different sets of muscarinic receptors that are found in cerebellar, vestibular and/or autonomic nuclei in the dorsal brainstem [36]. Scopolamine could be acting at all of these locations to block the action of ACh. This would occur whether or not ACh acted synaptically or as a neurohumoral agent reaching its target receptors in the dorsal brainstem by way of the CSF. Neurohumeral intermediates The idea of a neurohumeral agent in the CSF as mediating motion sickness is not new. Although not identified in their paper, Crampton and Daunton proposed that a chemical was released from the region of the IIIrd ventricle into the CSF and diffused posteriorly to the caudal brainstem to affect neurons involved in producing the symptoms associated with motion sickness [12]. In their study, one of the cats with a successful silastic block in the posterior portion of the IIIrd ventricle did not exhibit motion sickness symptoms when exposed to vertical sinusoidal displacement. The authors cautioned about over interpretation of their results because of certain technical limitations in their experimental protocol. Nonetheless the idea of a substance entering into the CSF and thereby gaining access to receptors on sensory and effector neurons in the dorsal brainstem remained an intriguing possibility. In another study, Wang and Chinn placed a plastic barrier over the area postrema in dogs and found them to be no longer susceptible to motion sickness [27]. The notion of neurotransmitter release into the CSF is not new. A study by Obata and Takeda reported the presence of GABA in the 4th ventricle subsequent to stimulation of the cerebellum of the cat [37]. Some studies have examined the CSF for chemicals that may be related to motion sickness. One study determined that cats susceptible to motion sickness had lower baseline levels of vasopressin [38]. This study involved sampling the CSF in the rostral portion of the IVth ventricle [38]. Another study analyzed the constituents of CSF after motion testing but found no changes in a number of transmitter-related molecules [39]. Although a number of neurotransmitters, their precursors and metabolites, amino acids and other compounds were measured, ACh was not among them. In addition, the sampling occurred in the rostral part of the IVth ventricle where, due to the caudal flow of the CSF, it would not have been an advantageous site for detecting compounds released from the vestibulocerebellum. With regard to the presence of ACh it has been determined that low levels of ACh are normally present in the CSF in the rat [40,41] and human [42,43]. It is likely that neurotransmitter levels in the CSF, including ACh, in the CSF will fluctuate with the degree of central neural activity involving these neurotransmitters [40]. A search of the literature however, failed to find a report in which ACh levels were measured in the CSF as a result of motion stimulation. A number of studies have
demonstrated that exogenously applied ACh did affect the activity of neurons in the AP, a structure implicated in the production of emesis [15,16]. In the proposed model, the AP could be a target of the ACh but it is not the only target. Some previous studies suggested, based upon surgical removal of the AP, that it was not necessary for the expression of motion sickness symptoms [44–46]. In the proposed model the AP is but one of a number of targets for ACh and thus it is not essential. However, in the intact animal it certainly could be a target. However, other cholinergic targets exist in the autonomic nuclei in the dorsal brainstem and their direct activation by ACh could then activate the emetic centers to produce motion sickness symptoms. If the proposed hypothesis is correct it would provide an explanation for the finding that AP lesions do not eliminate the ability to elicit motion sickness. Cholinergic receptors Analysis of the distribution of cholinergic receptors within the dorsal brainstem suggests that neural sites containing either nicotinic and/or muscarinic receptors are likely to be involved either in the afferent pathways that provide the sensory inflow related to motion detection, or are on effector sites that play a role in the genesis of the symptoms associated with motion sickness. Cholinergic receptors have been demonstrated in the vestibular nuclear complex, the NTS, AP, DMX and the EMRF [18,19]. The presence of both nicotinic and muscarinic cholinergic receptors within the vestibular nuclei has been demonstrated anatomically, biochemically and physiologically [47–52,20,53]. Some of these receptors may mediate a fascilitatory effect on the neurotransmission between primary vestibular afferents and second order vestibular neurons within the vestibular nuclei [35]. All of these sites are located in the dorsal portion of the posterior medulla, directly beneath vestibulocerebellum. Thus, it is conceivable that ACh released from the vestsibulocerebellum in response to motion-induced vestibular stimulation could diffuse into the CSF of the IVth ventricle and thereby interact with these cholinergic receptors located on neurons in this dorsal brainstem region. The consequences of this would be direct activation of neural substrates that are involved in the production of symptoms associated with motion sickness, including palor, cold sweating, dizziness, GI distress, retching and vomiting. In addition, because the location of the vestibular nuclei is immediately beneath the floor of the IVth ventricle it is likely that the cholinergic receptors in these nuclei would also be activated. This activation could provide a positive feedback mechanism that would further activate the cholinergic afferents to the vestibulocerebellum resulting in additional release of ACh and further diffusion of ACh into the IVth ventricle. Testing the hypothesis This hypothesis can be best tested in animals that are susceptible to motion sickness but the probability of its validity can be initially determined in mice and/or rats. A straightforward approach would be to expose animals to vestibular stimulation and immediately after exposure withdraw a sample of CSF from the cisterna magna to see if it contains an increased levels of ACh. The concentration of ACh can be compared to the ACh levels in an animal not exposed to vestibular stimulation and to the levels of CSF withdrawn in the same animal prior to the vestibular stimulation. The use of both an inter-animal and intra-animal controls would clearly determine whether the ACh sample differences were due to vestibular stimulation and not the sampling procedure itself. A second experimental approach would be to inject ACh, or one of its agonists, (muscarinic and nicotinic agonists) into the 4th ventricle via the cisterna magna, in an animal, such as a cat or ferrit, that
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is susceptible to motion sickness to see if increasing the concentration of ACh in the CSF will result in the onset of motion sickness symptoms. In addition, since it is known that scopolamine is an effective anti-motion sickness medication, both ACh and scopolamine could be injected into the 4th ventricle to see if scopolamine would prevent or reduce the onset of motion sickness symptoms. These experiments are relatively straightforward and would provide initial evidence for or against the proposed hypothesis. It may be that the ‘‘curious” linkage between vestibular stimulation and the debilitating symptoms of motion sickness may be a result, at least in part, to the unfortuitous anatomical and biochemical relationship between the vestibular system, the cerebellum and the autonomic and emetic centers in the dorsal brainstem. Acknowledgement The author would like to sincerely thank Robbie Eisenman for reviewing this manuscript. References [1] Mehler WR. Observations on the connectivity of the parvicellular reticular formation with respect to a vomiting center. Brain Behav Evol 1983;23(1– 2):63–80. [2] Yates BJ, Grelot L, Kerman IA, Balaban CD, Jakus J, Miller AD. Organization of vestibular inputs to nucleus tractus solitarius and adjacent structures in cat brain stem. Am J Physiol 1994;267(4 Pt 2):R974–83. [3] Balaban CD. Projections from the parabrachial nucleus to the vestibular nuclei: potential substrates for autonomic and limbic influences on vestibular responses. Brain Res 2004;996(1):126–37. [4] Balaban CD. Vestibular autonomic regulation (including motion sickness and the mechanism of vomiting). Curr Opin Neurol 1999;12(1):29–33. [5] Balaban CD. Vestibular nucleus projections to the parabrachial nucleus in rabbits: implications for vestibular influences on the autonomic nervous system. Exp Brain Res 1996;108(3):367–81. [6] Balaban CD, Beryozkin G. Vestibular nucleus projections to nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve: potential substrates for vestibulo–autonomic interactions. Exp Brain Res 1994;98(2):200–12. [7] Balaban CD, Porter JD. Neuroanatomic substrates for vestibulo–autonomic interactions. J Vestib Res 1998;8(1):7–16. [8] Treisman M. Motion sickness: an evolutionary hypothesis. Science 1977;197(4302):493–5. [9] Money KE. Motion sickness. Physiol Rev 1970;50(1):1–39. [10] Reason JT, Brand JJ. Motion sickness. New York: Academic Press; 1975. [11] Oman CM. Motion sickness: a synthesis and evaluation of the sensory conflict theory. Can J Physiol Pharmacol 1990;68(2):294–303. [12] Crampton GH, Daunton NG. Evidence for a motion sickness agent in cerebrospinal fluid. Brain Behav Evol 1983;23(1–2):36–41. [13] Barmack NH, Baughman RW, Eckenstein FP, Shojaku H. Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J Comp Neurol 1992;317(3):250–70. [14] Lindstrom PA, Brizzee KR. Relief of intractable vomiting from surgical lesions in the area postrema. J Neurosurg 1962;19:228–36. [15] Carpenter DO, Briggs DB, Knox AP, Strominger N. Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. J Neurophysiol 1988;59(2):358–69. [16] Strominger NL, Hori N, Carpenter DO, Tan Y, Folger WH. Effects of acetylcholine and GABA on neurons in the area postrema of Suncus murinus brainstem slices. Neurosci Lett 2001;309(2):77–80. [17] Cortes R, Probst A, Palacios JM. Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in the human brain: brainstem. Neuroscience 1984;12(4):1003–26. [18] Hyde TM, Gibbs M, Peroutka SJ. Distribution of muscarinic cholinergic receptors in the dorsal vagal complex and other selected nuclei in the human medulla. Brain Res 1988;447(2):287–92. [19] Pedigo Jr NW, Brizzee KR. Muscarinic cholinergic receptors in area postrema and brainstem areas regulating emesis. Brain Res Bull 1985;14(2):169–77. [20] Wamsley JK, Lewis MS, Young 3rd WS, Kuhar MJ. Autoradiographic localization of muscarinic cholinergic receptors in rat brainstem. J Neurosci 1981;1(2):176–91. [21] Yates BJ, Miller AD. Physiological evidence that the vestibular system participates in autonomic and respiratory control. J Vestib Res 1998;8(1):17–25. [22] Johnson WH, Sunahara FA, Landolt JP. Importance of the vestibular system in visually induced nausea and self-vection. J Vestib Res 1999;9(2):83–7. [23] Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111(Suppl. 8A):106S–12S.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Motion sickness may be caused by a neurohumoral action of acetylcholine Leonard M. Eisenman * Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19038, USA
a r t i c l e
i n f o
Article history: Received 15 April 2009 Accepted 17 April 2009
s u m m a r y The mechanism by which motion stimulation results in the autonomic responses, known as motion sickness, has remained somewhat of an enigma. Neural connections between the vestibular nuclei and the autonomic and emetic centers in the brainstem have been described, but these appear to be relatively sparse. Thus, new or additional mechanisms seem warranted to account for this curious relationship. A new hypothesis is herein presented which posits that acetylcholine (ACh) acts as a neurohumeral agent to bring about the symptoms associated with motion sickness. Motion stimulation will activate primary vestibular afferents leading to activation of secondary vestibulocerebellar fibers, some of which are cholinergic, projecting to the vestibulocerebellar region of the posterior cerebellum. The acetylcholine, once released from these synaptic terminals diffuses into the CSF in the 4th ventricle. From there it gains access to the autonomic and emetic centers within the dorsal brainstem and can activate the cholinergic receptors in these nuclei to produce the symptoms characteristic of motion sickness. In similar fashion ACh would have access to the vestibular nuclei where it will facilitate transmission in these nuclei further reinforcing the vestibulocerebellar activity. This would serve as a positive feedback loop which will result in additional release of ACh from the cerebellum and further activation of the brainstem nuclei that result in the symptoms of motion sickness. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction The mechanism by which motion stimulation resulting from sea, train, air travel, etc., results in the visceral discomfort, commonly know as ‘‘motion sickness”, has remained an enigma. It is still not entirely clear how motion stimulation activates the visceral centers in the brainstem to produce the behavioral and autonomic responses, including ‘‘stomach awareness”, nausea, cold sweating, peri-oral and facial pallor, feeling of body warmth, dizziness, retching and recurrent vomiting experienced during motion sickness. As an explanation for these phenomena it might be surmised that there are extensive connections between the vestibular system and the autonomic and emetic centers in the brainstem. While there is some evidence for this anatomical linkage, it appears to be fairly limited [1–7]. Therefore, it seems reasonable to seek additional or other mechanisms by which the curious linkage between vestibular stimulation and motion sickness might arise. It is not intuitively obvious why such a linkage should exist at all. Emesis understandably results from the body’s attempt to eliminate ingested toxins. Why emesis should be linked to a motion induced conflict between sensory inputs is unclear. One evolutionary hypothesis suggests it may be an accidental by-product of ‘‘sensory conflict” [8]. This theory of motion sickness suggests that conflicting sensory inputs are necessary for motion sickness to develop [9– * Tel.: +1 215 593 7317; fax: +1 215 923 3808. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.04.031
11]. The evolutionary explanation as to why vestibular stimulation would result in such a debilitating condition, namely motion sickness, remains an open question. In this paper an alternative explanation is offered in the hope that it will be of heuristic value and stimulate further experimentation to determine its validity. The hypothesis is based on the premise that motion sickness is an accidental result of the anatomical relationships between the cerebellum, ventricular system and the dorsal brainstem. It encompasses the idea of a neurohumoral linkage, rather than direct synaptic connections between vestibular inputs and the visceral motor outputs [12]. In the present paper this concept is revisited and revised to incorporate acetylcholine (ACh) as the neurohumoral agent. Whereas previous work has suggested neural areas surrounding the 3rd ventricle as the site from which the suspected neurohumoral substance is released, the present hypothesis suggests the vestibulocerebellum as the proposed site from which the neurohumoral agent, ACh is released. In the following discussion the hypothesis will be presented first and then selected pertinent data will be reviewed in the light of this new mechanism for motion sickness. The hypothesis The hypothesis described below is summarized in Fig. 1. The peripheral vestibular apparatus, including the semicircular canals and the otolithic organs (utricle and saccule) provide an abundant input to the vestibular nuclei, located in the dorsal medullary
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[19,17,20]. This would establish a positive feedback loop further activating the vestibulocerebellar afferents to the vestibulocerebellum resulting in additional release of ACh into the CSF. The positive feedback would potentiate the ACh effects on the neurons in the dorsal brainstem visceral nuclei and thus exacerbate motion sickness symptoms. This positive feedback loop might also account for the residual effects of motion sickness still present after the vestibular stimulation is no longer present, e.g. when someone experiencing motion sickness due to sea travel continues to feel queasy and uncomfortable when once again on dry land. Does it fit with existing data?
Fig. 1. This is a diagrammatic representation of the hypothetical framework for the generation of motion sickness symptoms as a result of motion stimulation. The labyrinth sends primary vestibular afferents to the vestibular nuclei (block arrow) and the vestibulocerebellum (thin black arrow). The presumed neurotransmitter in this pathway is glutamate (block arrow). The vestibular nuclei project to the autonomic nuclei in the dorsal brainstem (thin clear block arrow) and also to vestibulocerebellum via axonal projections and part of this pathway is cholinergic (curved arrow – ACh). The ACh released in the vestibulocerebellum diffuses (light gray block arrows – ACh) into the CSF of the 4th ventricle (IVth ventricle). ACh then diffuses (light gray block arrows-ACh) into the neurophil of the dorsal brainstem where there are nicotinic and/or muscarinic cholinergic receptors within the area postrema (AP) and the autonomic nuclei (e.g. NTS, DMX and ECRF). In addition, ACh diffuses into the vestibular nuclei in the dorsal brainstem where it interacts with cholinergic receptors to fascilitate the transmission of afferent input to the vestibulocerebellum. In this latter action it provides a positive feedback to enhance the further release of ACh from the vestibulocerebellar fibers. The end result is the activation of the autonomic and emetic nuclei and the genesis of motion sickness symptoms (sad face).
brainstem and also to the ventral regions of the posterior cerebellum, known as the vestibulocerebellum. In addition to these primary afferents there is also a robust projection from the vestibular nuclei to this same region of the cerebellum. This latter secondary projection system uses acetylcholine as one of its neurotransmitters [13,7]. It is highly probable that vigorous motion-induced vestibular stimulation would result in significant release of ACh from secondary vestibulocerebellar cholinergic mossy fiber afferents to the vestibulocerebellum. In many mammals and primates, including the human, the vestibulocerebellum is positioned directly over the 4th ventricle, which is situated between cerebellum and the brainstem. In particular, nuclei involved in autonomic regulation are situated within the dorsal portion of the brainstem immediately below the 4th ventricle. These nuclei include the nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMX), emetic centers located in the reticular formation (EMRF) and also the area postrema (AP), a circumventricular organ that is known to be a chemoreceptor trigger zone for emesis [14– 16]. The present hypothesis suggests that ACh released by the vestibulocerebellar afferents acts not only synaptically, to affect it’s postsynaptic targets, the granule cells in the vestibulocerebellar region, but that under the influence of vigorous vestibular stimulation sufficient ACh is released and diffuses into the underlying CSF in the 4th ventricle. Once in the 4th ventricle ACh would have access to neurophil in the dorsal brainstem and the autonomic nuclei where it could bind with cholinergic receptors found on many of the neurons in these visceral nuclei [17,18]. The neurohumoral activation of both synaptic and potentially extrasynaptic, ACh receptors would then mediate autonomic responses associated with motion sickness. In addition, ACh could also bind to cholinergic receptors found on the neurons within the vestibular nuclei
It is well known that an intact vestibular system is essential for the generation of motion sickness [9,21,22]. Thus, activation of vestibular afferents is necessary, but how does this input then activate the autonomic nuclei (NTS, DMX, EMRF, AP etc.) in the dorsal medullary brainstem that form an integral part of the emetic circuitry [23,19,24]? These autonomic and emetic areas are in close proximity to the vestibular nuclei, especially the medial and inferior vestibular nuclei. The most reasonable conclusion would be that there are neuroanatomical connections between the vestibular system and the visceromotor nuclei in the brainstem that account for the effects of vestibular stimulation on the generation of autonomic symptoms associated with motion sickness. However, while there is neuroanatomical and electrophysiological evidence that such linkages exist, these studies suggest that the connections are surprisingly sparse especially given the robust and long duration of the motion sickness response [1,2,4–6]. This raises the question as to whether vigorous motion stimulation might result in the activation of a different mechanism by which such stimulation affects dorsal brainstem structures responsible for the autonomic responses associated with motion sickness. Cerebellar involvement Primary vestibular afferents project to the vestibular nuclei and cerebellum. These primary vestibular afferents appear to use glutamate as their neurotransmitter [25]. Second order fibers from the vestibular nuclei project to the spinal cord, cerebellum, oculomotor centers and thalamus. With regard to the cerebellar target, it has been demonstrated that some of these projections are cholinergic [13,26]. Although the suggestion has been made that the vestibulocerebellar region is necessary for the elicitation of vomiting and other symptoms related to motion sickness, these data are inconsistent [27,28]. It is quite clear however, that this vestibulocerebellar region receives abundant input from the vestibular system [29]. Anatomically, the vestibulocerebellar region forms part of the roof over the posterior aspect of the IVth ventricle, which is situated between the cerebellum and the dorsal brainstem. Vestibular stimulation would therefore result in the activation of cholinergic synapses within the vestibulocerebellum. The released ACh could bind with receptors on postsynaptic granule and unipolar brush cells within the vestibulocerebellar region and then be degraded by cholinesterases. In addition to this however, it is proposed that certain types of vigorous motion-induced vestibular stimulation would result in significant release of ACh from these presynaptic terminals permitting its diffusion into the CSF. Once in the CSF high levels of ACh would be rapidly hydrolyzed by acetylcholinesterase before it could reach the dorsal brainstem. However, it appears that high concentrations of ACh inhibit acetylcholinesterase [30]. Thus, sufficient ACh may remain and allow to function in a neurohumoral fashion. If this were the case then ACh could have access to neurons in the dorsal brainstem that possess both synaptic and
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possibly extrasynaptic cholinergic receptors. There is evidence to suggest that neurotransmitters are found within the CSF and that substances can diffuse into the brain parenchyma from the CSF {44} once in the neurophil both synaptic and extrasynaptic receptors can serve as binding sites for neurotransmitters [31–33]. There is also abundant evidence that neurons in the dorsal brainstem autonomic nuclei mentioned above express both nicotinic and muscarinic cholinergic receptors [34,17–19,25]. Thus, direct neurohumoral activation of the autonomic nuclei involved in motion sickness by ACh released from the cerebellum is feasible. It has also been shown that the transmission between first and second order vestibular neurons is facilitated by cholinergic agonists and disfacilitated by cholinergic antagonists [35]. In agreement with the above observations is the finding that scopolamine, a competitive inhibitor of muscarinic cholinergic receptors, is the most effective drug for the prevention of motion sickness [10,36]. Scopolomine’s site of action is still unclear but it likely involves different sets of muscarinic receptors that are found in cerebellar, vestibular and/or autonomic nuclei in the dorsal brainstem [36]. Scopolamine could be acting at all of these locations to block the action of ACh. This would occur whether or not ACh acted synaptically or as a neurohumoral agent reaching its target receptors in the dorsal brainstem by way of the CSF. Neurohumeral intermediates The idea of a neurohumeral agent in the CSF as mediating motion sickness is not new. Although not identified in their paper, Crampton and Daunton proposed that a chemical was released from the region of the IIIrd ventricle into the CSF and diffused posteriorly to the caudal brainstem to affect neurons involved in producing the symptoms associated with motion sickness [12]. In their study, one of the cats with a successful silastic block in the posterior portion of the IIIrd ventricle did not exhibit motion sickness symptoms when exposed to vertical sinusoidal displacement. The authors cautioned about over interpretation of their results because of certain technical limitations in their experimental protocol. Nonetheless the idea of a substance entering into the CSF and thereby gaining access to receptors on sensory and effector neurons in the dorsal brainstem remained an intriguing possibility. In another study, Wang and Chinn placed a plastic barrier over the area postrema in dogs and found them to be no longer susceptible to motion sickness [27]. The notion of neurotransmitter release into the CSF is not new. A study by Obata and Takeda reported the presence of GABA in the 4th ventricle subsequent to stimulation of the cerebellum of the cat [37]. Some studies have examined the CSF for chemicals that may be related to motion sickness. One study determined that cats susceptible to motion sickness had lower baseline levels of vasopressin [38]. This study involved sampling the CSF in the rostral portion of the IVth ventricle [38]. Another study analyzed the constituents of CSF after motion testing but found no changes in a number of transmitter-related molecules [39]. Although a number of neurotransmitters, their precursors and metabolites, amino acids and other compounds were measured, ACh was not among them. In addition, the sampling occurred in the rostral part of the IVth ventricle where, due to the caudal flow of the CSF, it would not have been an advantageous site for detecting compounds released from the vestibulocerebellum. With regard to the presence of ACh it has been determined that low levels of ACh are normally present in the CSF in the rat [40,41] and human [42,43]. It is likely that neurotransmitter levels in the CSF, including ACh, in the CSF will fluctuate with the degree of central neural activity involving these neurotransmitters [40]. A search of the literature however, failed to find a report in which ACh levels were measured in the CSF as a result of motion stimulation. A number of studies have
demonstrated that exogenously applied ACh did affect the activity of neurons in the AP, a structure implicated in the production of emesis [15,16]. In the proposed model, the AP could be a target of the ACh but it is not the only target. Some previous studies suggested, based upon surgical removal of the AP, that it was not necessary for the expression of motion sickness symptoms [44–46]. In the proposed model the AP is but one of a number of targets for ACh and thus it is not essential. However, in the intact animal it certainly could be a target. However, other cholinergic targets exist in the autonomic nuclei in the dorsal brainstem and their direct activation by ACh could then activate the emetic centers to produce motion sickness symptoms. If the proposed hypothesis is correct it would provide an explanation for the finding that AP lesions do not eliminate the ability to elicit motion sickness. Cholinergic receptors Analysis of the distribution of cholinergic receptors within the dorsal brainstem suggests that neural sites containing either nicotinic and/or muscarinic receptors are likely to be involved either in the afferent pathways that provide the sensory inflow related to motion detection, or are on effector sites that play a role in the genesis of the symptoms associated with motion sickness. Cholinergic receptors have been demonstrated in the vestibular nuclear complex, the NTS, AP, DMX and the EMRF [18,19]. The presence of both nicotinic and muscarinic cholinergic receptors within the vestibular nuclei has been demonstrated anatomically, biochemically and physiologically [47–52,20,53]. Some of these receptors may mediate a fascilitatory effect on the neurotransmission between primary vestibular afferents and second order vestibular neurons within the vestibular nuclei [35]. All of these sites are located in the dorsal portion of the posterior medulla, directly beneath vestibulocerebellum. Thus, it is conceivable that ACh released from the vestsibulocerebellum in response to motion-induced vestibular stimulation could diffuse into the CSF of the IVth ventricle and thereby interact with these cholinergic receptors located on neurons in this dorsal brainstem region. The consequences of this would be direct activation of neural substrates that are involved in the production of symptoms associated with motion sickness, including palor, cold sweating, dizziness, GI distress, retching and vomiting. In addition, because the location of the vestibular nuclei is immediately beneath the floor of the IVth ventricle it is likely that the cholinergic receptors in these nuclei would also be activated. This activation could provide a positive feedback mechanism that would further activate the cholinergic afferents to the vestibulocerebellum resulting in additional release of ACh and further diffusion of ACh into the IVth ventricle. Testing the hypothesis This hypothesis can be best tested in animals that are susceptible to motion sickness but the probability of its validity can be initially determined in mice and/or rats. A straightforward approach would be to expose animals to vestibular stimulation and immediately after exposure withdraw a sample of CSF from the cisterna magna to see if it contains an increased levels of ACh. The concentration of ACh can be compared to the ACh levels in an animal not exposed to vestibular stimulation and to the levels of CSF withdrawn in the same animal prior to the vestibular stimulation. The use of both an inter-animal and intra-animal controls would clearly determine whether the ACh sample differences were due to vestibular stimulation and not the sampling procedure itself. A second experimental approach would be to inject ACh, or one of its agonists, (muscarinic and nicotinic agonists) into the 4th ventricle via the cisterna magna, in an animal, such as a cat or ferrit, that
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is susceptible to motion sickness to see if increasing the concentration of ACh in the CSF will result in the onset of motion sickness symptoms. In addition, since it is known that scopolamine is an effective anti-motion sickness medication, both ACh and scopolamine could be injected into the 4th ventricle to see if scopolamine would prevent or reduce the onset of motion sickness symptoms. These experiments are relatively straightforward and would provide initial evidence for or against the proposed hypothesis. It may be that the ‘‘curious” linkage between vestibular stimulation and the debilitating symptoms of motion sickness may be a result, at least in part, to the unfortuitous anatomical and biochemical relationship between the vestibular system, the cerebellum and the autonomic and emetic centers in the dorsal brainstem. Acknowledgement The author would like to sincerely thank Robbie Eisenman for reviewing this manuscript. References [1] Mehler WR. Observations on the connectivity of the parvicellular reticular formation with respect to a vomiting center. Brain Behav Evol 1983;23(1– 2):63–80. [2] Yates BJ, Grelot L, Kerman IA, Balaban CD, Jakus J, Miller AD. Organization of vestibular inputs to nucleus tractus solitarius and adjacent structures in cat brain stem. Am J Physiol 1994;267(4 Pt 2):R974–83. [3] Balaban CD. Projections from the parabrachial nucleus to the vestibular nuclei: potential substrates for autonomic and limbic influences on vestibular responses. Brain Res 2004;996(1):126–37. [4] Balaban CD. Vestibular autonomic regulation (including motion sickness and the mechanism of vomiting). Curr Opin Neurol 1999;12(1):29–33. [5] Balaban CD. Vestibular nucleus projections to the parabrachial nucleus in rabbits: implications for vestibular influences on the autonomic nervous system. Exp Brain Res 1996;108(3):367–81. [6] Balaban CD, Beryozkin G. Vestibular nucleus projections to nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve: potential substrates for vestibulo–autonomic interactions. Exp Brain Res 1994;98(2):200–12. [7] Balaban CD, Porter JD. Neuroanatomic substrates for vestibulo–autonomic interactions. J Vestib Res 1998;8(1):7–16. [8] Treisman M. Motion sickness: an evolutionary hypothesis. Science 1977;197(4302):493–5. [9] Money KE. Motion sickness. Physiol Rev 1970;50(1):1–39. [10] Reason JT, Brand JJ. Motion sickness. New York: Academic Press; 1975. [11] Oman CM. Motion sickness: a synthesis and evaluation of the sensory conflict theory. Can J Physiol Pharmacol 1990;68(2):294–303. [12] Crampton GH, Daunton NG. Evidence for a motion sickness agent in cerebrospinal fluid. Brain Behav Evol 1983;23(1–2):36–41. [13] Barmack NH, Baughman RW, Eckenstein FP, Shojaku H. Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J Comp Neurol 1992;317(3):250–70. [14] Lindstrom PA, Brizzee KR. Relief of intractable vomiting from surgical lesions in the area postrema. J Neurosurg 1962;19:228–36. [15] Carpenter DO, Briggs DB, Knox AP, Strominger N. Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. J Neurophysiol 1988;59(2):358–69. [16] Strominger NL, Hori N, Carpenter DO, Tan Y, Folger WH. Effects of acetylcholine and GABA on neurons in the area postrema of Suncus murinus brainstem slices. Neurosci Lett 2001;309(2):77–80. [17] Cortes R, Probst A, Palacios JM. Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in the human brain: brainstem. Neuroscience 1984;12(4):1003–26. [18] Hyde TM, Gibbs M, Peroutka SJ. Distribution of muscarinic cholinergic receptors in the dorsal vagal complex and other selected nuclei in the human medulla. Brain Res 1988;447(2):287–92. [19] Pedigo Jr NW, Brizzee KR. Muscarinic cholinergic receptors in area postrema and brainstem areas regulating emesis. Brain Res Bull 1985;14(2):169–77. [20] Wamsley JK, Lewis MS, Young 3rd WS, Kuhar MJ. Autoradiographic localization of muscarinic cholinergic receptors in rat brainstem. J Neurosci 1981;1(2):176–91. [21] Yates BJ, Miller AD. Physiological evidence that the vestibular system participates in autonomic and respiratory control. J Vestib Res 1998;8(1):17–25. [22] Johnson WH, Sunahara FA, Landolt JP. Importance of the vestibular system in visually induced nausea and self-vection. J Vestib Res 1999;9(2):83–7. [23] Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111(Suppl. 8A):106S–12S.
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