EXPERIMENTAL STUDIES ON MOTION SICKNESS by MELVILLE SCHACHTER• B.So. A thesis submitted to the Faculty of Graduate Studies and Research in partial fUlfilment of the requirements for the degree of Master of Science in Physiolog Me Gill University, llontreal. August, 1942 w.sc. Physiology Malville Schachter Experimental ttudies on Motion Sickness The stability ot acetyl choline in blood was studied in vitro. A method has bean developed permitting the complete preservation ot acetyl choline in blood tor a period ot one week in a tonB suitable tor assay. The syndrome ot motion sickness was studied in a large number or doge. Though the symptoms or motion sickneas were round almost identical with those resulting rrom circulating acetyl choline, no trace or circulating acetyl choline could be detected in the blood ot motion-sick animals. Atropine, papaverine and neuro-traaent1n were round to hava no signiricant action in dalaying the vomiting due to motion. Bulbocapnine, however, was round to have some delaying action. The mechanism underlying the cardio-vascular action ot tha bile salts was determined in acute experiments on oats·and dogs. TABLE OF CONTEN!I'S PAR!!' ONE Page Introduction ••••••••••••••••••••••••••••••••••••••••••• 1 The In Vitro Preservation of Acetyl Choline in Blood ,,, 6 The Effect of Acid pH on Acetyl Choline Stability in Blood •••••••••••••••••••••••••••••• 7 The Effect of Prostigmine on Acetyl Choline Stability in Blood •••••••••••••••••••••••••••••• 10 The Effect of Acid plus Prostigmine on Acetyl Choline Stability in Blood •••••••••••••••••••••• 11 The Combination of Acid and Prostigmine as a Means of Effecting Prolonged Preservation of Acetyl Choline in Blood in a Form Suitable for Subse- quent Assay ••••••••••••••••••••••••••••••••••••• 12 Summary ••••••••••••••••••••••••••••••••••••••••••• 13 !!'he "Interfering Effect" on the Bio-Assay of Acetyl Choline Produced by the Action of Acid on Blood ••••• 19 The Amount of Acetyl Choline Detectable in Normal Whole Blood ••••••••••••••••••••••••••••••••••••••••••••••• 23 Studied on Seasickness ••••••••••••••••••••••••••••••••• 26 Severe Vomdting and Its Effect on Blood Acetyl Choline ••••••••••••••••••••••••••••••••••••••••• 26 s,rmptomatology of Experimental Seasickness (Motion Sickness) and Blood Acetyl Choline Studies •••••• 27 Symptomatology Resulting from InJected Proatigmine and Acetyl Choline in Unanaestheti&ed Animals ••• 31 Symptomatology Resulting from Labyrinth Stimulation in Humans ••••••••••••••••••••••••••••••••••••••• 36 The Predisposition to Motion Sickness by Subminimal Doses of Prostigmine •••••••••••••••••••••••••••• 38 Is There a Correlation between Susceptibility to Motion Sickness and Susceptibility to In~eoted Acetyl Choline? ••••••••••••••••••••••••••••••••• 40 Acetyl Choline and the Central Nervous System • • • • • 43 The Therapeutic Action of Certain Drugs in Motion Sickness •••••••••••••••••••••••••••••••••••••••• 46 Summary and Conclusions ••••••••••••••••••••••••••• ~2 PART TWO The Cardio-Vascular Action of the Bile Salts with Regard to Inhibition of Cholinesterase ••••••••••••••••••••• 53 Mechanis. of Systemic Action of Bile Salt in the Intact Animal ••••••••••••••••••••••••••••••••••• 56 Action of Bile Salt on the Isolated Frog Rectus Abdominis Muscle •••••••••••••••••••••••••••••••• 60 Summary and Conclusions ••••••••••••••••••••••••••• 63 TABLE OF CONTENTS {concluded} Page Summary of thesis •••••••••••••••••••••••••••••••••••••• 67 Bibliography ••••••••••••••••••••••••••••••••••••••••••• 68 ACKNOWLEDGMENTS I wish to express m7 appreciation of the invaluable suggestions and criticism which I have received from Prof. B. P. Babkin, who suggested the problem. I also wish to thank Dr. s. Dworkin, with whom the experimental work was conJointly carried out, tor much helpful advice. In addition, I wish to thank Miss Esther Dworkin for some technical assistance. EXPERIMENTAL STUDIES ON MOTION SICKNESS PART ONE INTRODUCTION Very little experimental work has been carried out on seasickness. We have had to speculate on the possible underlying physiological mechanisms largely trom the super­ ficial observations and empirical therapy of clinicians. As in all il'lStanoes where e:x:aot knowledge is lacking a large number of theories has been suggested. The following are the most common, though not all the suggested theories. to account for the cause ot seasickness. (1) Visceral Disp&Acement This theory is supported by Lengenbagger (1936), Pop­ pen {1939) and by Smith and Feiling. (Quoted by Brooks, 1939.) The theory suggests that the disturbances ot motion sickness result tram pressure and traction exerted on sympa­ thetic nerve plexuses in the epigastric region and trom vagus nerve irritation. There is. however, no direct evidence to support thia theory. Antagonistic evidence is turniehed by the tact that the jolting movements of horseback riding rarely produce motion sickness, yet the swaying movements ot camel riding do (Toubib, 1937). Further evidence against the tmportanoe ot 2. the visceral theory was obtained in our studies. (2) Psychogenic Theorz (Autoauasestion) Elder (1937) believes psychic factors to be of pri­ mary tmportanoe in seasickness. He believes that other conditions are secondary in importance to a stimulus of cere­ bral origin. Though psychic tactors may occasionally be of impor­ tance in motion sickness, the basic cause of the disturbance undoubtedly lies elsewhere. That mental states occasionally provoke the appearance of seasickness is readily borne out by the well known tact that apprehensive people may became ill aboard ship before it leaves port. Brooks {1939} cites Pavlov as having established a conditioned reflex to motion sickness in dogs. We also succeeded in establishing such a response in our studies. The fact, however, that people who have no fear of becoming seasick, and experimental animals, where psychic factors are removed, readily became seasick, proves that the basic cause is not psychic. (3) Visual Theory This theory states that the visual strain involved in the observation of moving ob~eots is a strongly prediw.posing factor in the production of motion sickness. Brooks (1939) claims that those with eye trouble are particularly sensitive to motion sickness. Poppen (1939) believes eyestrain adds to the accumulation of afferent tmpulsea in seasickness. He says, however. that visual impulses may be either stimulatory or inhibitory since some Victims are soothed by observing the 3. horizon whereas others are aggravated. The evidence indicates that visual factors can only be of very secondary importance in seasickness. Blind people became seasick (Brooks, 1939). (4) Acidosis s. Jones (1928) claims 99 per cent. of eases of vomit­ ing at sea are accompanied by increased acidity and acetonuria. Oriel (1927), from a study of patients at sea, concluded that glucose relieves seasickness symptoms by causing diuresis, abolishing acetonuria and reducing ammonia excretion. Acidosis. however, must really be regarded as an effect rather than cause of seasickness. Its appearance in patients at sea who have been seasick for several days is probably a result of the self-imposed starvation. In our experiments, susceptible animals became acutely ill in a matter of minutes, when acidosis could not possibly have developed. (5} Somatic Receptors That overstimulation of a large number of somatic reeeptors resulting in a "multiplicity of unusual stimuli" to sensory nerves regarding body position is the cause of the distress of motion sickness is held by Poppen (1939). He claims a nervous fatigue is produced "resulting from a bom­ bardment of afferent impulses on secondary nerve centres. This bombardment results from excessive interplay of tensions and pressures among the viscera and skeletal organization." The difficulty with such a hypothesis is that innu­ merable conditions may involve visceral mov~ent and muscular interplay without resulting in the symptoms of motion sick- ness. Ordinary exercise would fulfil the criteria of this hYpothesis and yet it never results in nausea and vomiting. (6l Labzrinthine Theorz Of all the theories mentioned this is the only one which is supported by substantial evidence. It postulates that overstimulation of the labyrinth is the primary factor in the production of seasickness. According to Fisoher (1930), evidence in support of this theory was obtained by Kreidl, who observed that seasickness could not be produced in experimental animals after labyrinthect~. It is also a common observation that deaf-mutes and others suffering from VIII N. degeneration are particularlY immune to seasickness. (SJoberg, 1929; Brooks, 1939; Alvarez, 1941.) In this con­ nection it is of interest to note that according to Ar.mstrong (1939) individuals with dead labyrinths seldom became airsick. Further experimental studies have shown that prolonged stimulation of the labyrinth may markedly atteot the tunctions of the autonamic nervous system, especially the parasympathe­ tic. In experiments on humans, Lebensohn (1931), studying gastric motility during cold-irrigation of the ear (as a laby­ rinth stimulus) and during oar-sickness, observed in both oases marked changes in gastric motility. Roeoavilla (1922) observed in normal individuals that galvanic or 4alorio stimu­ lation of the labyrinth almost always produced a violent gas­ tric contraction. Similar observations have been made by Spiegel and Demetriades (1924) and by LeHeux and deKleyn (1932). Kotyza (1937), from experimental studies, concluded that sti­