TABLE OF CONTENTS . ............................................................................... I INTRODUCTION 3 ................................................. I1. PRINCIPLE AREAS of INVESTIGATION 3 . ....................................................................... A Behavioral Measures 3 . ....................................................................................... 1 Pica 4 . ...................................................................................... 2 CTA 4 . ................................................................................. 3 Anorexia 4 . ............................................................ B Effective Stimulus Parameters 5 C . Neuroanatomy and Physiology ........................................................... 5 . ............................................................................. 1 Vasopressin 5 . .......................................................................... 2 Area Postrema 6 . ............................................................................ 3 Vagus Nerve 6 . ................................................................. 4 Immunoc y toe hemis try 6 . ........................................................................ D Species Differences 7 . 111 CONCLUSIONS . ................................................................................ IV REFERENCES 8 . V LIST OF FIGURES . Figure 1 Mean Food Intake and Body Weight by Rats Exposed to Off-Vertical .................................................................................... Rotation 10 . Figure 2 Mean Food Intake and Body Weight by Rats Exposed to Parabolic ....................................................................................... Flight 11 . Figure 3 Mean Fluid Intake by Rats Prior to and Following Exposure to Parabolic ....................................................................................... Flight 12 . . ................................................... VI APPENDIX I RESEARCH PAPERS 13 . . V APPENDIX 11 PAPERS PRESENTATED AT .............................................................. SCIENTIFIC MEETINGS 15 2 1. INTRODUCTION categories. These categories are used to organize the presentation of the results and to facilitate the Motion sickness typically is considered a discussion of motion sickness in animal models. bothersome artifact of exposure to passive Thus, the results of these studies of motion motion in vehicles of conveyance. This sickness in animal models are org with the condition seldom has significant impact on the following categories: (a) behavid measures of health of individuals because it is of brief the phenomenon, (b) stimuli that are effective €or duration, it usually can be prevented by simply producing the phenomenon, (c) nernnanatomical avoiding the eliciting condition and, when the structures and physiological events that are conditions that produce it are unavoidable, related to the phenomenon, and (d) differences sickness dissipates with continued exposure. between species in the elicitation of the However, unavoidable motion sickness is a phenomenon. malady that can have significant effects on the The first two of these categories, behavioral performance of af'fected individuals. Because the measures and effective stimuli, were addressed in susceptibility of individuals to motion sickness the initial experiments because mulis from these cannot be predicted with precision, some two categories of studies were fundamental to individuals can be seriously affected if they are planning other experiments. After behavioral required to work in an environment that produces measures had been subjected to initial validation motion sickness. The affliction of individuals of and appropriate parameters were established for unknown susceptibility by this malady can eliciting stimulation, studies were conducted to become important when sickness could arise examine neural structures and physiological during periods where complicated but necessary events that were related to motion sickness. As performance is demanded. The occurrence of studies related to these questions progressed, the space motion sickness during entry into or rem issue of species differences in the response began from space flight is one possible case of this to arise and this was subjected to both type. Important human activities are required retrospective analysis and direct experimental during launch and landing of the Space Shuttle, examiaation. precisely the times when "space sickness" can occur. A. Behavioral Measures There is some debate about the equivalence of motion sickness produced in ground-based studies Frank sickness, or vomiting, is the only and "space sickness". However, pund-based universally accepted response that defines motion studies provide certain benefits over flight sickness in all species. None-the-less, many studies. Gmd-based studies can be Conducted at other responses (e.g., pallor, increased salivation, considerable cost savings, the necessary control defecation) are commonly considered to be part of conditions can be included with experimental the general syndrome of motion sickness. In rigor, and the appropriate number of subjects an studies of motion sickness in humans MUS^^, a be used to address the experimental questions. measure that is obtained only by self report, Because there are numerous similarities between commonly is used as a prominent prodromal motion sickness and space sickness, it appears symptom of sickness. that better knowledge of motion sickness could Nausea and other prodramal symptoms that are significantly benefit the understanding and future deected by selfneport can be used m humans, but study of space sickness. there are no reliable methods for obtaining self The studies conducted in this research project reports of symptoms in animals. Because of examined several aspects of motion sickness in this, two alternative methods are used to assess animal models. A principle objective of these the development of motion sickness in animal studies was to investigate the neuroanatomy that models. One system is to use rating scales based is important in motion sickness with the on the assessment of various responses that are objectives of examining both the utility of putative prodromal symptoms. Such scales have putative models and defining neural mechanisms been developed for use with cats, squirrel that are important in motion sickness. monkeys and chimpanzees (Fox, 1992). An extensive discussion of rating scales with animals is presented by Daunton (1989). The II. PRINCIPLE AREAS of second strategy is to use specific responses (eg., INVESTIGATION conditioned taste aversion) that are thought to be related to neural or physiological mechanisms For purposes of exposition, the studies and that underlay motion sickness. This strategy has research findings have been classified into four been used with animals that do not have a 3 complete emetic reflex and as multiple or equally crucial for the production supplemental indices of sickness (Ossenkopp & sickness in man and CTA in animals. Ossenkopp, 1985). Experimental studies were conducted to evaluate pica, conditioned taste aversion (CTA), and anorexia as putative measures of motion sickness. Pica was proposed as a measure of gastric distress and motion sickness by Mitchell (1977). This response was selected for assessment because it results as increased responding rather than as reduced responding to be described. A paramount concern in this which is common with many of the other regard is that the relationship between vomiting putative measures for animal models (Fox, and CTA is not isomorphic in either cats or 1990). CTA is the measure most commonly squirrel monkeys (Fox er al., 1990). Because asserted and best documented for assessing nausea CTA is not precisely related to the universal and sickness in animals. Anorexia commonly symptom of motion sickness in species with a occurs with motion sickness in humans and complete emetic reflex, the validity of CTA as a anecdotaIIy also in animals that have a complete prodromal symptom in these species and as a emetic reflex. Consequently this measure was primary index of sickness in rodents that fail to evaluated in several experiments. vomit is uncertain. 1. Pica. 3. Anorexia. Pica was studied in rats with sickness induced Two experiments were conducted to directly by vertical and off-vertical rotation at 150°/s. test anorexic and conditioning effects of motion. No reliable pica response was produced by this These effects were assessed by exposing animals treatment when appropriate groups were used to to either off-vertical rotation or to parabolic control for confounded effects of food deprivation. flight using 15 parabolas in a Lear jet. Anorexia Pica could be induced by exposing fooddeprived was assessed in rats permitted to feed for 2h per animals to motion, but food deprivation itself day with exposure to motion on test days also induced pica. OccWing just prior to the feeding session. CTA This result is in conuast to data reported by was conducted using procedures described Mitchell (1977). It should be noted, however, elsewhere (Fox & Daunton, 1982). that studies showing pica in rats have used The mean daily consumption of food in the experiment using off-vertical rotation is shown intense motion stimuli (e.g., 75Qoo/s) or severe gasmc irritants as inducing treatments. The in Figure 1. Food consumption increased and body weight decreased over the initial days of purpose of these preliminary studies in this project was to investigate whether pica could be adaptation to the restricted feeding regimen (2 Wday) una intake stab%ed by about Day 11. produced in rats using moderate motion conditions that were representative of marments Using Day 19 (the day preceding exposure to motion) as a baseline, anorexia was present on known to produce motion sickness in man and other animals. In that regard the answer to the the day of exposure to motion (on Day 20, experimental question was that pica was not a psc.001) but intake on Days 21 & 22 did not differ from baseline (p.39). Body weight was useful measure. suppressed on each of the three days following 2. CTA. expasure to motion (ps<.003). It has long been recognized that CTA can be The mean daily consumption of food in the experiment using parabolic flight is shown in produced by numerous interventions, including motion, that are known to produce gastric Figure 2. Again, food consumption i n das the animals adapted to the restricted feeding distress in humans and animals. This relationship between CTA and "internal mdaise” schedule (2 h/day) with body weight reflecting an initial decrease (first 5 days) followed by a has led to widespread interest in using CTA to assess several forms of sickness arising from nonnal tendency to increase. On Day 12 the rats gasmc disruption in animal models. Several were transported to the flight line and loaded on observations have i n d i d t hat CTA may be a the airplane to determine whether this activity useful measure of motion sickness in animal would affect the dependent measures. No effects models. Important among these is the where seen on either food intake or body weight demonstration that an intact vestibular system is with this procedure (Fcl). With Day 18 as a 4 baseline, anorexia was present immediately after the flight (Day 19) and 48 h later (Day 20). , Food consumption 72 h after the flight did not differ from that preceding the flight (p.80). Food intake was suppressed immediately and 24 moderate stimulation that is h following flight (ps<.002) but by 48 h after the flight food intake did not differ from the baseline (p>. 11 ). The effects if parabolic flight on CTA are species. shown in Figure 3. Intake of flavored fluid by Conditioned aversion can be produced in animals in the Control and Fiight groups did not roden that is of the differ prior to the flight, but in the test following magn g in squirrel parabolic animals in the Conaol group consumed monkeys, chimpanzees, and humans (Fox & more fluid than did the animals in the Flight Daunton (1982); Fox et d., 1984). Further, this group (p<.OOl). It should be noted that the Same stimulation can produce CTA in both cats strength of conditioning is rather weak. There and squirrel monkeys (Fox et d., 1990). Thus, was no significant suppression of intake in it is clear that conditioned aversions do not animals exposed to flight. Rather, these animals depend on severe mdcm challenges. failed to increase intake as was seen in animals Detailed examination of eliciting stimuli in from the Control group. Thus, a release from squirrel monkeys reflected that exposure to neophobia in Control animals with a failure to stimuli of increasing intensity to humans also observe this release in Fight animals appears to elicited more severe sickness in the monkey (Fox create this difference. et al., 1982). An important result in this study, The observed suppression of food intake could however, was the finding that stimuli that are be a form of anorexia similar to that produced extremely provocative for humans are effective during prolonged exposure of animals to hyper- for the squirrel monkey only when there is a gravity during centrifugation, or to hypo-gravity requirement for the animal to maintain posture. during orbital flight. The coincident emergence When animals were exposed to provocative of anorexia and CTA is consistent with the stimuli' (cross-coupled stimulation) while proposal that the rats became motion sick during movement was restricted at both the neck and the altered gravity during the brief exposures to waist, the same stimulus that elicited sickness parabolic flight. The magnitude of flight-induced with waist nstraint only no longer was effective. anorexia is as great as, or greater than that Thus, it appears that a requirement for postural produced by a form of passive, crosscoupled control during passive motion is necessary if stimulation that is very provocative for Rumans. motion sickness is to be elicited. A)Anorexia following parabolic flight was Examination of the role of vision in motion present for 48 h while that produced by rotation sickness produced the first demonsmuon of was absent after only 24 h. vomiting in cats and squirrel monkeys by visual Informal observations regarding anorexia were stimulation alone (Daunton et ul., 1985). conducted in both cats and squirrel monkeys to Sickness induced by visual stimulation alone is begin examination of this effect in animals with known in man and is very disruptive in certain a complete emetic reflex. Both cats and squiml instances (e.g., "simulator siclmess), but this has monkeys were repeatedly observed to eat the food not been shown previously in an animal model. normally contained in their diets (cat food and With regard to the problem of prediction, it was bananas respectively) within a few minutes (e.g., shown in this research that animals more prone less than 5 min) after vomiting. These to sickness by passive, whole-body stimulation observations indicate that anorexia is not also were more likely to become sick by necessarily present when the UnivexsaUy accepted optokinetic stimulation alone. indicator of motion sickness occurs. These effects have not been satisfactorily resolved as not formal experiments were conducted to test C. Neuroanatomy and P hyslQlOgy this issue further. 1. Vasopressln. Vasopressin (AVP) is elevated in humans 8. Effective Stimulus Parameters during nports of nawa and following vomiting (see Fox, 1992 for a review). Plasma AVP is The specific parameters of stimulation that dramatically eIevatcd in cats following vomiting effectively produce motion sickness in animal but the resting level of AVP in blood plasma 5 does not differ among cats that are selected to be GABAergic terminals in the area postrema, highly susceptible or very resistant to linear nucleus tractus solikus, area sub-postrema, and acceleration. On the other hand, AVP in gelatinous nucleus closely resembles that of cerebrospinal fluid (CSF) is not elevated vagal afferent projections @'Ameli0 et following motion sickness, but resting levels of 1988). In addition, the depletion of G AVP in CSF are lower in animals that vomited immunoreactive in these areas after elec during motion than in those animals which did stimulation of the vagus nerve seems to not vomit (Fox er al., 1987). The precise that at least part of the GABAergic activity mechanism for the release of AVP during shown here corresponds with vagal afferents. motions sickness could not be determined. The additional demonstration of substance P Systemic injection of AVP at dosages calculated immunoreactivity in this study implies there to produce levels equivalent to those observed may be important neuromodulatory functions following vomiting failed to produce vomiting or mediated by mmpeptib. to influence the onset of vomiting in cats that were susceptible or resistant to to linear acceleration (Unpublished Data). D. Species Differences 2. Area Postrema. W e co nducting the studies discussed above Experiments using the lesion technique to to evaluate behavioral measures of and effective examine the role of the area postrema showed stimuli for motion sickness it became that: (a) The area postrema is not involved in increasingly obvious that stimuli that elicited CTA that is produced by motion in rats (Sutton sickness and the syndromes observed in different et ol., 1988); (b) Neither CTA nor vomiting are species varied greatly. For example, linear crucially dependent on the area postrema in either acceleration, particularly earth-vertical cats or squirrel monkeys (Fox, Corcoran & acceleration, is an especially effective stimulus Brizzee, 1990). In combination with work by for eliciting motion sickness in cats while Borison and Borison (1986), these findings vertical axis rotation is remarkably noneffective. conmbuted to a reevaluation of the role of the On the other hand, vertical axis rotation is very area postrema in vomiting induced by motion provocative for the squirrel monkey while linear (Daunton et al., 1987). several authors have now acceleration has only minimal effectiveness with proposed theories which include several additid this species. brainstem and/or circumventricllal structures in Species differences can occur in rather closely the emetic response (see Fox, 1992 for related species where similar reactions to stimuli references). might be expected. For example, although vertical axis rotation is very provocative for 3. Vagus Nerve. squirrel monkeys, we were unable to make rhesus A possible role for the vagus nerve in monkeys motion sick with this stimulus responses to motion is implied by results (Corcoran, Fox, & Daunton, 1990). In fact, showing that the vagus nerve is crucial to CTA bothanecdomlandexperimentalevidenceindi~ induced in rodents by exposure to motion (Fox & that the rhesus monkey is highly resistant to McKenna, 1988). Combined with other research, motion sickness. Workers in the Russian space this finding shows that both vestibular and program have reported "space sickness" but there gastric neural systems contribute to the have been no well controlled studies reporting on formation of CTA when motion is the stimulus. these effects (see Daunton, 1990 for a review of The specific mechanism by which gastric these points). circuitry functions is unknown (Fox, Sutton, & Difference of this type complicate the selection McKenna, 1988), but we did provide evidence of appropriate animal models for studying the indicating that gastric afferents of the rat remain emetic reflex in general and motion sickness or active for an extended period following brief the space adaptation syndrome in particular. physiological stimulation (Nijiima et ul., 1987; Animal models will be crucial to the discovery 1988). and understanding of neurophysiological mechanisms of these phenomena, but 4. irnmunocytochemlstry. considerable research will be required before Preliminary evidence indicating a role for the answers come forth. vagus nerve either in motion sickness or in adaptation to stimuli producing motion sickness has been shown. Using immunocytochemistry we showed that the distribution pattern of 6 motor coordinati 111. CONCLUSIONS All of the behavioral responses that have been examined as measures of motion sickness in animals are less than ideal. The only response that is universally accepted as a valid measure is vomiting. On initial consideration this appears lying down or going to sleep. In this regard it to be a serious weakness in this area of research. However, it should be recognized that no other measures have been universally accepted for the assessment of motion sickness in humans. The would suggest that motion most commonly used additional measure in simply be an unfortunate ou human studies is nausea, but the assessment of processes of adjusring the nwomuscular system nausea, even in humans can be quite inaccurate. to new, atypical environmental conditions. Furthermore, there are no recognized Although the specific mechanisms that may be physiological correlates of nausea in humans, involved in such processes are obscure at this further complicating the assessment of this time, discovery of the physiology and neural response in animals. changes that underlie adaptation may predict the The issue of prediction of susceptibility to mechanisms that elicit motion sickness. motion sickness also is difficult. Significant attention has been directed to the problem of prediction in humans with only minimal success. While we found some evidence for predictive value in the level of AVP in CSF, this effect was not highly predictive and significant work would be required to understand this relationship adequately. As is the case in humans, piasma AVP was dramatically elevated in cats following vomiting, but there was no evidence in this research to indicate that the level of system A W was predictive of susceptibility to motion sichess. It is now abundantly clear that previous conceptions of the area postrema as a vomiting center in motion sickness were premature and incorrect. This conceptualization arose, in part, from over-interpretation of lesion experiments before many of the techniques of neuroscience that are in common use today were available. With present knowledge, many workers now propose by that the emetic reflex is mediated via circuitry in several circumventricular and brainstem regions. Imporrant work remains to provide understanding of the specific neural mechanisms of the response that is so important in disease and travel by modem conveyances. A gend hypothesis that was developed during the course of this research project is that motion sickness is a phenomenon that may reflect only one of the outcomes of the more general effects of adaptation to unusual environmental conditions. Motion sickness arises when organisms are subjected to passive motion that results in atypical linear forces on the vestibular system. Passive motion of this type can elicit significant and pervasive adaptive responses in many systems other than the emetic reflex (e.g., 7 IV. REFERENCES Fox, R. A., & Daunton, N. G. (1982). Conditioned feeding suppression in rats Borison, H. L,, & Borison, R. (1986). Motion produced by cross-coupled and simple motions. sickness reflex arc bypasses the area postrema Aviation, Space and Environmental in cats. Experimental Neurology, 92, Medicine, 53, 218-220. 723-737. Fox, R. A., Daunton, N. G., & Coleman, J. D'Amelio, F., Gibbs, M. A., Mehler, W. R., (1982). Susceptibility of the squirrel monkey Daunton, N. G., & Fox, R. A. (1988). to several different motion conditions. Immunocytochemid localization of glutamic Neuroscience Abstracts, 8, 698. acid decarboxylase (GAD) and substance P in neural areas mediating motion-induced emesis. Fox, R. 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