Effects Of Estrogen Receptor Antagonist Tamoxifen On Susceptibility To Various Models Of Motion Sickness In Mice And Rats

Motion sickness (MS) is observed in humans exposed to unfamiliar motion. Usually, the four cardinal symptoms of cold sweating, pallor, nausea and vomiting are preceded by some combination of prodromal features such as lethargy, salivation, enhanced visceral awareness, dizziness and panting. According to different circumstances, MS includes seasickness, vehicle sickness, airsickness, space sickness and simulator sickness.MS is the integration of vestibular, visual, proprioceptive and other sensory stimulus. Accelerating motion is exopathic causes, the sensitive vestibular end organ is the internal cause. Due to different motion models, MS is induced by different response access. Airsickness and space sickness are induced by angular accelerations, which stimulate primarily the semicircular canals. Seasickness and vehicle sickness are initiated by linear accelerations, which stimulate primarily the otolith organs.It is required for research on MS to establish an experimental model. Vomiting is the criterion of gastrointestinal malaise in most studies dealing with MS. Since rodents are unable to vomit, they are not routinely used in studies dealing with MS. Many attempts have been made to use behavioral criteria other than emesis to detect for MS.Clinical and preclinical studies have found sex-specific differences in susceptibility to MS and females are more susceptible than males. Symptoms of MS induced by an optokinetic drum were significantly different between females and males. Significant gender differences in MS were also observed in mice, rats, squirrel monkeys, chimpanzee and Suncus murinus. Gender differences in susceptivity to MS were found in human between 8-39 years old. There were less gender differences in human beyond 40 years old, especially 60 years old. In addition, after administering tamoxifen, a selective estrogen receptor antagonist, two sisters, both breast cancers, felt sick less frequently after different kinds of transport or motion. Therefore, estrogen and estrogen receptor antagonist would play an important role in genesis of MS.In the present study, we try to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS in the different animal models for MS.Objective: To establish the convenient and feasible animal models of MS in mice and rats for research on the mechanism of MS while to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS on these models.Methods and results:1. Establishment of experimental animal model for MSFollowing 1 min of rotation at 250 rpm, the latency of licking a hindpaw on the hot plate in mice was significantly prolonged (P<0.05). Furthermore, following 60 min of rotation at 70 rpm, mice showed significant increase in kaolin intake, and showed significant decrease in total distances and activity of the open field test compared with unrotated mice (P<0.05). In addition, kaolin intake was also significantly increased following 120 min of rotation in rats (P<0.05). Therefore, rotation-induced analgesia, pica and spontaneous activity could be the behavioral indices of experimental MS in mice. Of course, pica have already been recognized also an index of MS in rats.2. Examination of prophylactic-MS drugs (scopolamine) on animal model of MSScopolamine, the classic prophylactic-MS drugs, at dose of 0.1, 0.3 and 1.0 mg/kg (ig) significantly decreased latency of licking a hindpaw and kaolin intake in mice, and kaolin intake in rats following rotation, respectively. The results verified the feasibility of animal model of MS. So, it seems that latency of licking a hindpaw in mice and kaolin intake in rats or mice are sensitive parameters for evaluating the effects of prophylactic-MS drugs.However, scopolamine (0.15-0.60 mg/kg) did not significantly decrease the total distances and activity in open field test following rotation. It is possible because of central inhibitory effect of scopolamine and scopolamine is lack of specificity on this model.3. Effect of chemical labyrinthectomy on MSUnder anesthesia with 30 mg/kg intraperitoneally of sodium pentobarbital, mice received bilateral intratympanic each side 0.04 ml of the arsanilic acid solution. The needle was inserted through the tympanic membrane until resistance by the auditory ossicles was encountered, and then the solution was injected within 3-4 s. Following each side injection the ear canal was tightly packed with gelfoam to prevent against leaking of injected solution. Sham-lesioned mice received bilateral intratympanic injections of 0.04 ml of isotonic saline. It is convinced that vestibular apparatus was damaged by vestibular function evaluation using contact righting reflex and swimming test. Moreover, light and electron microscopy further confirmed the damage of vestibular apparatus.Following rotation, mice with chemical labyrinthectomy showed decreases in the latency of licking a hindpaw and kaolin intake and increases in total distance and activity of the open field test, indicating that chemical labyrinthectomy antagonized MS induced by rotation in mice. It is consistent with labyrinthectomy abolished pica behavior in rats. Therefore, a functioning vestibular system is very necessary for the perception of MS.4. Effects of ovariectomy and tamoxifen on susceptivity to MSThe postrotational latency of licking a hindpaw and kaolin intake in mice were significantly decreased 4 h after administratering tamoxifen at dose of 20 mg/kg (ig). In addition, the postrotational latency of licking a hindpaw in mice significantly decreased following administering intragastrally with tamoxifen at dose of 2 mg/kg once daily for 21 consecutive days. The results suggested that tamoxifen had inhibitory effect on susceptivity to MS in mice. However, tamoxifen with single or repeated administration at dose of 15 mg/kg did not decrease kaolin intake in rats following rotation.The postrotational latency of licking a hindpaw significantly increased 28 d after ovarietomy in mice, suggesting that ovarietomy could not inhibit MS indexed as latency of licking a hindpaw. However, postrotional kaolin intake significantly decreased 30 d after ovarietomy in rats, indicating that estrogen could also influence susceptivity to MS. Thus, estrogen and selective estrogen receptor antagonist tamoxifen have different effects on susceptivity to MS on different animal models of MS.Conclusion: It is suggested that rotation-induced hot-plate responses, pica behavior and spontaneous activity in mice and pica behavior in rats could be the convenient and feasible indices of animal model for research on the mechanism of MS. Furthermore, estrogen and tamoxifen have different effects on susceptivity to MS on different animal models of MS. Tamoxifen could reduce susceptivity to MS indexed as hot-plate responses and pica behavior in mice, whereas ovariectomy increased the postrotational hot-plate latency, suggesting increase of sensitivity to MS in mice. In addition, the effects of ovariectomy and tamoxifen on susceptivity to MS in rats await further repeated verification through experiments.