assessing-autonomic-behavioral-effects-passive-motion-rats-using

Assessing the Autonomic and Behavioral Effects of Passive Motion in Rats using Elevator Vertical Motion and Ferris-Wheel Rotation

The overall goal of this study is to assess the autonomic and behavioral effects of passive motion in rodents using the elevator vertical motion and ...

Second Military Medical University

Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss-induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3'-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 μg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders. 

Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats.

Many studies have demonstrated sex and age differences in motion sickness, but the underlying physiological basis is still in controversy. In the present study, we tried to investigate the potential correlates of endocrine and/or neuronal activity with sex and age differences in rats with motion sickness. LiCl-induced nausea symptom was evaluated by conditioned gaping. Motion sickness was assessed by measurement of autonomic responses (i.e., conditioned gaping and defecation responses), motor impairments (i.e., hypoactivity and balance disturbance) after Ferris wheel-like rotation, and blood hormone levels and central Fos protein expression was also observed. We found that rotation-induced conditioned gaping, defecation responses and motor disorders were significantly attenuated in middle-aged animals (13- and 14-month-age) compared with adolescents (1- and 2-month-age) and young-adults (4- and/or 5-month-age). LiCl-induced conditioned gapings were also decreased with age, but was less pronounced than rotation-induced ones. Females showed greater responses in defecation and spontaneous locomotor activity during adolescents and/or young-adult period. Blood adrenocorticotropic hormone and corticosterone significantly increased in 4-month-old males after rotation compared with static controls. No significant effect of rotation was observed in norepinephrine, epinephrine, β-endorphin and arginine-vasopressin levels. The middle-aged animals (13-month-age) also had higher number of rotation-induced Fos-labeled neurons in the spinal vestibular nucleus, the parabrachial nucleus (PBN), the central and medial nucleus of amygdala (CeA and MeA) compared with adolescents (1-month-age) and young-adults (4-month-age) and in the nucleus of solitary tract (NTS) compared with adolescents (1-month-age). Sex difference in rotation-induced Fos-labeling was observed in the PBN, the NTS, the locus ceruleus and the paraventricular hypothalamus nucleus at 4 and/or 13 months of age. These results suggested that the sex and age differences in motion sickness may not correlate with stress hormone responses and habituation. The age-dependent decline in motion sickness susceptibility might be mainly attributed to the neuronal activity changes in vestibulo-autonomic pathways contributing to homeostasis regulation during motion sickness.

Sex and Age Differences in Motion Sickness in Rats: The Correlation with Blood Hormone Responses and Neuronal Activation in the Vestibular and Autonomic Nuclei.

Enhanced cholinergic activity contributes to the production of complex autonomic manifestations of motion sickness (MS). However, whether anti-cholinergics exert their anti-MS effects through central or peripheral actions remained unclarified. In the present study, we investigated the effects of mecamylamine (MEC) and scopolamine (SCOP) on rotation-induced gastrointestinal symptoms (conditioned gaping and defecation), locomotion disturbances (hypoactivity and impaired balance performance), hypothermia as well as Fos expression in vestibulo-autonomic regions in rats. We also observed the effects of hexamethonium (HEX) and methyl scopolamine (MSCP) on those MS behavioral responses. The efficacy of all these drugs on rotation-induced emesis and other MS symptoms in cats was also examined. We found that intragastric administration of MEC and SCOP inhibited rotation-induced gaping and defecation in rats, but only MEC showed a dose-dependent manner. MEC aggravated rotation-induced balance disorder and failed to attenuate rotation-induced hypothermia as the SCOP did. MEC was more effective for inhibiting Fos expression in the caudal vestibular nucleus and nucleus of solitary tract than SCOP. Intraperitoneal injection of HEX and MSCP also significantly alleviated rotation-induced gastrointestinal symptoms, and showed benefit to balance performance in rats. In cats, MEC, SCOP and HEX had prophylactic effects against rotation-induced emesis and salivation, and deceased non-retching/vomiting symptoms, but MSCP only attenuated emesis. It suggested that MEC and SCOP might alleviate gastrointestinal symptoms of MS via inhibiting peripheral autonomic nervous system and central vestibulo-autonomic pathways. The nicotinic acetylcholine receptor inhibitors like MEC might be new candidates against gastrointestinal symptoms induced by MS or other vestibular disorders.

Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions.

Article	Year
Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats. Frontiers in neuroscience\| PubMed ID: 27507932	2016
Sex and Age Differences in Motion Sickness in Rats: The Correlation with Blood Hormone Responses and Neuronal Activation in the Vestibular and Autonomic Nuclei. Frontiers in aging neuroscience\| PubMed ID: 28261089	2017
Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions. Neuropharmacology\| PubMed ID: 30543811	2019

Leilei Pan

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