Etiologic significance of arginine vasopressin in motion sickness.

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146-D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose-response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.

Facilitation of adaptation and acute tolerance to stressful sensory input by doxepin and scopolamine plus amphetamine.

This work characterizes a new methodologic and pharmacologic approach to control terrestrial and space motion sickness (SMS). The experimental design allowed separate evaluation of drug action on susceptibility and adaptability, and used repeated measures to approximate the chronic stressful motion of microgravity. Daily exposure to cross-coupled angular acceleration for 5 consecutive days demonstrated that the efficacy of doxepin and scopolamine plus amphetamine in the prevention of autonomic system dysfunction was not only apparent on the first test day (P < .01), but was also evident in the substantially enhanced resistance developed over the 5-day test period (P < .01) as compared with placebo. This indicates that daily use of these medications does not diminish therapeutic efficacy (tolerance). The efficacy of doxepin was anticipated because it possesses pharmacologic properties similar to those of established anti-motion sickness drugs. Comparable efficacy after doxepin loading for 4 hours, 3 days, or 21 days suggests a mechanism distinct from its antidepressant effects, possibly related to its potent antihistaminergic actions. Use of doxepin has operational significance to the National Aeronautics and Space Administration, in comparison with current preparations of scopolamine plus amphetamine, because of doxepin's minimal impact on cognitive performance, and most importantly, its favorable pharmacokinetic profile, particularly its long half-life.

Autonomic function and plasma catecholamines following stressful sensory stimuli.

This experimentation defined a limited role for epinephrine in the autonomic nervous system function and the nausea that occurred following motion sickness testing. Individual responses to stressful sensory stimuli and nausea, as reflected by rising peripheral levels of epinephrine, were not significantly diminished upon repeated exposure and adaptation to the stressor. However, subjects who demonstrated more robust elevations of epinephrine in response to nausea displayed higher resistances to stressful motion stimuli. Modulation of peripheral catecholaminergic function with dexamethasone, or scopolamine plus amphetamine, suggested that altered autonomic nervous system function and nausea following motion sickness testing were not mediated by peripheral catecholamine receptor stimulation. Marked differences were noted in individual responses to drug and systemic responses of epinephrine and norepinephrine. It is possible that responses in epinephrine to motion sickness testing may predict resistance to stressful motion, and represent a peripheral manifestation of some as yet unknown central event of etiologic relevance.

The relationship between space sickness and preflight diet.

The nine astronauts who flew three Skylab missions during 1973 and 1974 were on carefully planned diets. Each astronaut selected his preferences from a list of approximately 70 food items, from which dietitians developed a rotating sequence of six daily menus. In addition to strict control of the inflight diet, each crewman consumed his planned diet for 21 days preflight and for 18 days postflight. While the amount consumed at each particular meal was largely discretionary, all deviations from the planned meals (which were few) were fully documented. Diets were controlled to provide adequate calcium, phosphorus, and protein because of bone and muscle losses observed on previous flights. Each day's menu had a similar elemental composition; if any particular item was not consumed, supplements in the form of capsules or tablets were prescribed the next day to make up for the shortfall. However, the dieticians did not so carefully control the relative proportions of carbohydrate, fat, and protein (though meticulous records were kept), which were instead selected somewhat incidentally as menus were constructed around each astronaut's food preferences. There are several possible physiologic determinants for food preferences and the regulation of dietary macro-nutrients. Monozygotic twins chose more similar intakes of total energy, protein, fat, and carbohydrate than did dizygotic twins, suggesting a genetic component of dietary regulation. The biosynthesis of neurotransmitters is directly influenced by the availability of their precursor nutrients, such as tryptophan for serotonin and choline for acetylcholine. Diet affects behavior, and it has been suggested that dietary self-selection by rats is regulated by effects of the diet on brain neurotransmitters. Some preflight variables relating to fluid, electrolyte and cardiovascular status, and to environmental exposures, have previously been found to have significant relationships to space sickness. The purpose of this study was to determine if diet could be another factor contributing to space sickness, since diet determines so much of physiology and behavior.

beta-Endorphin and arginine vasopressin following stressful sensory stimuli in man.

This experimentation partially defines, for the first time, the response of beta-endorphin (ENDO) in man during tests designed to elicit nausea and motion sickness. These responses are similar to those associated with arginine vasopressin (AVP) and adrenocorticotropin (ACTH) to the extent that all hormones rise in response to motion sickness (p < 0.003). Repeated exposure diminished motion-induced release of ENDO (p < 0.005) and AVP (p < 0.004) despite a three-fold increase in resistance to motion stimuli. Higher post-stress levels of AVP (p < 0.04) and ACTH (p < 0.02) were correlated with greater resistance to motion sickness. These data support the hypothesis that release of AVP is a significant link between stressful motion and motion-induced nausea and other autonomic system changes. Further, resistant individuals apparently can tolerate higher peripheral levels of AVP before nausea results. Peripheral release of ENDO and ACTH may follow release of AVP; however, given the extensive and complex functional interactions that exist between AVP and the opiate systems, it is not yet possible to define a clear role for ENDO in the etiology of motion sickness.

Investigation of anti-motion sickness drugs in the squirrel monkey.

Early attempts to develop an animal model for anti-motion sickness drugs, using dogs and cats; were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti-motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800-1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti-motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3-6.0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Effects of coenzyme Q10 supplementation on exercise performance, VO2max, and lipid peroxidation in trained cyclists.

The effects of dietary supplementation with Coenzyme Q10 (CoQ10), a reputed performance enhancer and antioxidant, on physiological and biochemical parameters were examined. Ten male bicycle racers performed graded cycle ergometry both before and after being given 100 mg per day CoQ10 or placebo for 8 weeks. Analysis of variance showed a significant difference between groups for postsupplementation serum CoQ10. Although both groups demonstrated training related improvements in all physiological parameters over the course of the study, there were no significant differences between the two groups (p > .05). Both groups showed a 21% increase in serum MDA (an index of lipid peroxidation) after the presupplementation exercise test. After 8 weeks this increase was only 5%, and again was identical for both groups. Supplementation with CoQ10 has no measurable effect on cycling performance, VO2max, submaximal physiological parameters, or lipid peroxidation. However, chronic intense training seems to result in marked attenuation of exercise-induced lipid peroxidation.

New pharmacologic approaches to the prevention of space/motion sickness.

Fundamental approaches in selection of new agents for evaluation in prevention of space/motion sickness (SMS) are reviewed. The discussion centers on drugs under investigation at the Johnson Space Center. Methodology that employs the rotating chair for measuring SMS symptomatology and susceptibility is described. The most obvious approach to the development of new agents relies on selection of agents from drug classes that possess pharmacologic properties of established anti-motion sickness agents. A second approach selects drugs that are used to prevent emesis caused by means other than exposure to motion. The third approach relies on basic research that characterizes individual differences in susceptibility. The hypothesis is: detection of individual differences leads to identification of specific drugs, which target physiologic systems that show individual differences. These physiologic systems are targets for therapy and may play a role in the etiology of SMS. Two drugs that reduce susceptibility to SMS include dexamethasone and d(CH2)5Tyr(Me)AVP, a vasopressin (AVP)V1 antagonist. The latter peptide has demonstrated complete blockade of emesis and other significant symptoms in squirrel monkeys. These studies were predicated on observations that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistances. Investigations are underway to test a 0.5-mg intravenous dose in humans. Kappa opioid agonists inhibit AVP release and offer new therapeutic possibilities and advantages over AVP peptides. This review details the experimental data collected on AVP and adrenocorticotropin. The literature supports interrelated roles for AVP and opioid peptides in SMS. Experimental testing of kappa agonists is warranted because specific opioid agonists act at neuroanatomical sites causing nausea and vomiting. It is argued opioid receptors in the chemoreceptor trigger zone and vomiting center stimulate and inhibit the emetic response, respectively. The evidence suggests kappa and/or mu receptors at VC are involved in inhibition of emesis, whereas delta opioid receptors at CTZ are involved in stimulation of emesis.

Control of nausea and autonomic dysfunction with terfenadine, a peripherally acting antihistamine.

Terfenadine (Seldane) was administered to 14 male subjects in a randomized, double-blinded, and crossed-over design to assess the efficacy of this peripherally active antihistamine as an anti-motion sickness drug. Terfenadine possesses practically no central side effects. A Staircase Profile Test was administered 4 h following placebo or a single oral dose of terfenadine (300 mg). The study revealed a statistically significant therapeutic effect from terfenadine (p less than 0.05). This led us to conclude that because the drug does not or only poorly crosses the blood-brain barrier, a selective peripheral antihistamine (H1) action may be sufficient in the control of motion sickness induced through cross-coupled accelerative semicircular canal stimulation using a rotating chair. This finding implies that other peripherally acting agents might be found that possess even greater anti-motion sickness efficacy. The present research raises additional questions regarding current theories on the etiology of motion sickness, its associated autonomic system dysfunction, and the validity of assumptions that effective pharmacological agents must act centrally.

Is there a role for nonsedating antihistamines in motion sickness? Fallout from space research may soon benefit your patients.

The rotating chair test, a novel research technique for simulating motion sickness, is used to study the effect of nonsedating oral antihistamines in preventing or forestalling motion sickness. After receiving terfenadine, astemizole, doxepin, or placebo, four groups of male volunteers were rotated at accelerating speed, and they made head movements out of the axis of rotation until they perceived that vomiting would occur if additional head movements were made. Those pretreated with doxepin or terfenadine experienced a statistically significant prophylactic effect, as measured by increased tolerance to Coriolis stimulation. This suggests that selective peripheral H1 antihistamine action may protect against motion sickness.

Sodium concentration in saliva along the time course of experimental Coriolis sickness.

Procedures designed to evaluate the severity of motion sickness have included subjective reporting of changes in salivation. In order to increase objectivity, we studied the sodium concentration of saliva, which is directly related to the flow rate. Healthy adults with normal vestibular function underwent a modified Coriolis Sickness Susceptibility Index (CSSI) test, utilizing a staircase profile. Saliva was collected without interrupting the stimulus by means of cotton placed beneath the subject's tongue for one minute. Samples were obtained 5 min prior to stimulation, 30 and 45 min following stimulus onset, and/or upon reaching the "nausea II" endpoint. Saliva for analysis by atomic absorption spectrophotometry was obtained by centrifugation of the cotton. A significant difference in sodium concentration was found between the baseline and 30-min sample (p less than 0.01). Although the amount of salivation was rather variable, the pattern of changes in sodium concentration was similar in all experimental cases.

Mechanisms underlying the antimotion sickness effects of psychostimulants.

The major conclusions of this review are: 1) that selective enhancement of dopaminergic transmission, not noradrenergic, is sufficient to account for amphetamine-induced resistance and perhaps natural resistance to motion sickness; 2) the site of this enhanced dopaminergic transmission is probably within the basal ganglia; and 3) the neuropharmacology of the basal ganglia, but not the brainstem vestibular areas, can account for the therapeutic synergism of scopolamine and amphetamine. The therapeutic actions of psychostimulants may be dissociable from some of their side effects, particularly cardiovascular effects related to peripheral norepinephrine release. Drugs which target specific subtypes of dopaminergic receptors may serve this purpose.

Lack of effects of astemizole on vestibular ocular reflex, motion sickness, and cognitive performance in man.

Astemizole was orally administered to 20 subjects in a randomized, double-blind design to assess the efficacy of this peripherally active antihistamine as an antimotion sickness drug possessing no central side-effects. Measures of vestibular ocular reflex (VOR) were made to evaluate the agent as a selective vestibular depressant. Following 1 week of orally administered astemizole (30 mg daily), a Staircase Profile Test, a VOR test, and a variety of tests of cognitive performance were administered. These tests revealed no statistically significant effects of astemizole. This leads us to conclude that, although the drug probably reaches the peripheral vestibular apparatus in man by crossing the blood-vestibular barrier, a selective peripheral antihistamine (H1) action is inadequate to control motion sickness induced through cross-coupled accelerative semicircular canal stimulation in a rotating chair.

Mechanisms of selective attention and space motion sickness.

The neural mismatch theory of space motion sickness asserts that the central and peripheral autonomic sequelae of discordant sensory input arise from central integrative processes falling to reconcile patterns of incoming sensory information with existing memory. Stated differently, perceived novelty reaches a stress level as integrative mechanisms fail to return a sense of control to the individual in the new environment. Based on evidence summarized here, the severity of the neural mismatch may be dependent upon the relative amount of attention selectively afforded to each sensory input competing for control of behavior. Components of the limbic system may play important roles in match-mismatch operations, be therapeutically modulated by antimotion sickness drugs, and be optimally positioned to control autonomic output.

Hormonal responses of metoclopramide-treated subjects experiencing nausea or emesis during parabolic flight.

Metoclopramide was orally administered (10 or 20 mg) to 22 subjects, 75 min before parabolic flight. Serum levels of ACTH, EPI, NE, and vasopressin (AVP) were unaltered by metoclopramide. AVP and ACTH (1.2 and 36 pg.ml-1) were elevated 77 and 3.8-fold (92.3 and 135 pg.ml-1) following emesis, after 40 parabolas (68.7 and 140 pg.ml-1) and landing (8.7 and 79 pg.ml-1). Seven subjects displaying no nausea and no emesis demonstrated smaller elevations (8.2 and 2.2-fold). Of 15 vomiting subjects, 7 reported no nausea and had lower elevations of AVP with faster recoveries. These findings are consistent with Rowe's suggestion (1979) that nausea may correlate with AVP release. Inhibition of AVP release by fluid shifts during microgravity might account for our findings and astronaut-reported episodes of vomiting without nausea. Elevations in EPI followed emesis or exposure to 40 parabolas whether emesis occurred or not. Only emesis elevated NE (578 to 840 pg.ml-1).

Failure of metoclopramide to control emesis or nausea due to stressful angular or linear acceleration.

Orally administered metoclopramide (REGLAN) at doses of 10 or 20 mg, 75 min prior to either stressful linear acceleration (parabolic flight) or cross-coupled accelerative semicircular canal stimulation in a rotating chair was evaluated for its ability to prevent emesis or nausea II, respectively. Although metoclopramide is an effective antiemetic agent that enhances gastric emptying and prevents cancer chemotherapy-induced emesis, we were unable to demonstrate any significant (p less than 0.05) effects of this drug on motion sickness.

Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine.

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, we tested the efficacy of dexamethasone and metyrapone in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80% more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metyrapone[correction of metryapone] every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

Arousal and stability: the effects of five new sympathomimetic drugs suggest a new principle for the prevention of space motion sickness.

Sympathomimetic agents are frequent components in antimotion-sickness drug combinations because of their usefulness in counteracting the sedation caused by stressful motion or resulting from the administration of other antimotion-sickness drugs. The noradrenergic neurochemistry of the brain's arousal-attentional systems prompted us to evaluate the efficacy of five new sympathomimetic drugs and to further define the role of arousal in susceptibility to motion. Subjects were orally administered methamphetamine (20 mg), phenmetrazine (25 mg), phentermine (37.5 mg), methylphenidate (20 mg), or pemoline (75 mg) 2 h prior to taking a Staircase Profile Test. All of the drugs increased resistance to stressful coriolis stimulation by 80-120%. Methylphenidate and pemoline showed fewer side effects. These findings, interpreted in conjunction with the documented inefficacy of most anticholinergic and antihistaminergic drugs tested to date, suggest that sympathomimetic drugs or a generalized state of arousal can inhibit the development of motion sickness.

Double isotopic method using dansyl chloride for the determination of GABA in rat C6 astrocytoma cell cultures.

Methods are described for the quantitative measurement of GABA in culture. The method can be adapted to any amino acid or dansyl-chloride-reactive species. The sensitivity and selectivity of the procedure result from the double isotopic design in which (14C)-labeled internal standard was added to the samples before reaction with (3M)-labeled dansyl chloride. Values obtained by ion-exchange amino acid analysis of cultures agree closely with the values obtained by the double isotopic method. This method is sensitive enough to measure GABA intracellularly and the condition medium.

Endocrine correlates of susceptibility to motion sickness.

Motion sickness releases ACTH, epinephrine, and norepinephrine. We are interested in endocrine responses to motion sickness, in adaptive responses leading to the resolution of the syndrome, and in how antimotion-sickness drugs influence the endocrine responses. Susceptible or insusceptible subjects were administered antimotion-sickness drugs prior to stressful stimulation. Insusceptible subjects displayed more pronounced elevations of ACTH, epinephrine, and norepinephrine after stressful motion. Predrug levels of ACTH were higher in insusceptible subjects (p less than 0.01). Acute blockade of hormone responses to stressful motion or alteration of levels of ACTH by drugs was not correlated with individual susceptibility. No correlation was apparent between epinephrine and ACTH release. These endocrine differences may represent neurochemical markers for susceptibility to motion, stress, or general adaptability, and it may be that the chronic modulation of their levels might be more effective in preventing motion sickness than the acute blockade or stimulation of specific receptors.