Pharmacological profile of vestibular inhibitory inputs to superior oblique motoneurons.

Vestibulo-ocular reflexes (VOR) are mediated by three-neuronal brainstem pathways that transform semicircular canal and otolith sensory signals into motor commands for the contraction of spatially specific sets of eye muscles. The vestibular excitation and inhibition of extraocular motoneurons underlying this reflex is reciprocally organized and allows coordinated activation of particular eye muscles and concurrent relaxation of their antagonistic counterparts. Here, we demonstrate in isolated preparations of Xenopus laevis tadpoles that the discharge modulation of superior oblique motoneurons during cyclic head motion derives from an alternating excitation and inhibition. The latter component is mediated exclusively by GABA, at variance with the glycinergic inhibitory component in lateral rectus motoneurons. The different pharmacological profile of the inhibition correlates with rhombomere-specific origins of vestibulo-ocular projection neurons and the complementary segmental abundance of GABAergic and glycinergic vestibular neurons. The evolutionary conserved rhombomeric topography of vestibulo-ocular projections makes it likely that a similar pharmacological organization of inhibitory VOR neurons as reported here for anurans is also implemented in mammalian species including humans.

Neurotoxic mechanism of cinnabar and mercuric sulfide on the vestibulo-ocular reflex system of guinea pigs.

Cinnabar, a naturally occurring mercuric sulfide (HgS), has been combined with Chinese herbal medicine as a sedative for more than 2000 years. To date, its neurotoxic effect on the vestibulo-ocular reflex (VOR) system has not been reported. By means of a caloric test coupled with electronystagmographic recordings, the effect of commercial HgS and cinnabar on the VOR system of guinea pigs was studied. HgS or cinnabar was administered orally (1.0 g/kg) to Hartley-strain guinea pigs once daily for 7 consecutive days. A battery of electrophysiological, biochemical, and histopathological examinations were performed. The results showed that HgS induced a 60% caloric response abnormality (40% caloric hyperfunction and 20% hypofunction), whereas the abnormal responses appeared to be more severe (six out of six) in the cinnabar group. The Hg contents of whole blood and cerebellum were increased and correlated to their neurotoxic effects on the VOR system, indicating that both insoluble HgS and cinnabar could be absorbed from the gastrointestinal tract and distributed to the cerebellum. Although the vestibular labyrinth revealed no remarkable change under light microscopy, loss of Purkinje cells in the cerebellum was detected, and the enzymatic Na(+)/K(+)-ATPase activity of cerebellum (a higher inhibitory center of the VOR system) was significantly inhibited by HgS and cinnabar. Moreover, cerebellar nitric oxide (NO) production was increased significantly. Hence, we tentatively conclude that the increased Hg contents in the cerebellum following oral administration of HgS and cinnabar were responsible, at least in part, for the detrimental neurotoxic effect on the VOR system. Potentially, decreasing Na(+)/K(+)-ATPase activity and increasing NO production within the cerebellar regulatory center are postulated to mediate this VOR dysfunction caused by the mercurial compounds and cinnabar.

Optokinetic and vestibulo-ocular reflex adjustment by GABA antagonists.

We determined if high and low doses of anti-GABAergic drugs have opposite effects on the visuo-vestibular activity in pigmented rats and examined a possible correlation with the level of GABA in the related structures. First, the horizontal optokinetic and vestibulo-ocular reflexes of most animals were depressed by high doses of anti-GABAergic drugs (10(-3) M purified picrotoxin or 10(-6) M picrotoxin in unpurified vegetal extract). Simultaneously, a drop in GABA level in the cerebellum and posterior brainstem was detected. Second, after a subsequent injection (1 ml) of the diluted extract (10(-13) M picrotoxin), the reflexes returned to normal despite the fact that no correlation with the GABA level was found. These results demonstrate that small doses of anti-GABAergic drugs reverse the depressive effect created by large doses of these drugs on the oculomotor system, and even adjust the reflexes to the stimulation. This adjustment, without correlation with the GABA level, suggest a powerful effect of very low dose of the drug to modulate either the activity of the cerebellar inhibiting input or of the vestibular nuclei neurons or to trigger the adaptation by other neurotransmitter systems involved in the performances of the reflexes.

Click-evoked vestibulocollic reflexes in torticollis.

A total of 26 patients with torticollis were studied using a recently developed technique for recording vestibulocollic reflexes from the sternocleidomastoid muscles in addition to conventional caloric tests of vestibular function. Previous reports of abnormalities of vestibulo-ocular reflexes in these patients were confirmed with just fewer than half having significant canal pareses or directional preponderances (nine of 20 tested). In addition, there was a high incidence of abnormal click-evoked vestibulocollic reflexes (17 of 26 tested), which were not simply the result of prior treatment with botulinum toxin, nor due to unequal levels of muscle activation. In patients never previously treated with botulinum toxin (14 patients), the effect almost always consisted of suppressed responses in the sternocleidomastoid muscle ipsilateral to the direction of head turning. Because responses were not abnormal in all patients tested, and more commonly so in those with a history of torticollis of > or = 5 years (eight of nine patients) than in de novo patients, we suggest that the changes are more likely to be compensatory than causal.

Effects of Ginkgo biloba extract (EGb 761) on the guinea pig vestibular system.

Previous studies have demonstrated that the administration of Ginkgo biloba extract (EGb 761) improves the compensation of the vestibular syndrome induced by transection of the VIIIth nerve. To investigate the mechanisms at play, the vestibular nuclei of alert guinea pigs were perfused with EGb 761. This perfusion always induced a stereotyped reversible postural syndrome that was the mirror image of the syndrome provoked by the unilateral lesion of the otolithical receptors. This result supports the hypothesis that EGb 761 has a direct excitatory effect on the lateral vestibular nuclei (LVN) neurons. In a second step, we quantified the horizontal vestibuloocular reflex (HVOR) of the normal guinea pig following IP injection of EGb 761. In normal guinea pig, IP administration of EGb 761 led to a reversible, dose-dependent decrease of the HVOR gain without affecting the phase of the reflex. These data help to explain the therapeutic effects of EGb 761 during vestibular syndromes and strongly suggest an impact at the neuronal level.

Mislocalizations of visual elevation and visual vertical induced by visual pitch: the great circle model.

The elevation visually perceived as eye level (VPEL) changes linearly with the pitch of an illuminated visual field. The magnitude of influence is only slightly less when the visual field contains only two dim vertical lines in darkness than when it is complexly structured and normally illuminated. Pitching a visual field consisting of only a single line in darkness produces an influence that is only slightly smaller than the 2-line stimulus. The slopes of the VPEL-vs.-pitch functions for the complex room, 2-line stimulus, and 1-line stimulus are +0.63, +0.56, and +0.52 respectively. Although VPEL is systematically influenced by the pitch of the 2-line stimulus, the orientation of a small line within a frontal plane that is visually perceived as vertical is unaffected. However, when the two lines are pitched by equal amounts in opposite directions, the offset of VPV from true vertical changes linearly with pitch magnitude but VPEL is unaffected. These results are identical to those obtained when the two vertical lines are rolled within the frontal plane, a result that depends on some identities between roll and pitch: roll of two parallel lines in the same direction influences VPV but not VPEL; roll of the two lines in opposite directions influences VPEL but not VPV. The interaction between stimulus conditions and discriminations demonstrates that separate mechanisms are in control of VPEL and of VPV. The slope of the VPEL-vs.-pitch function increases exponentially with line length for the 1-line stimulus (space constant = 15.1 degrees). Summation of influences on VPEL for two lines horizontally separated by 50.3 degrees is as great as for two coextensive lines. The above results are predicted from the Great Circle Model which assumes (1) central projection on a spherical approximation to an erect stationary eye; (2) the sign and magnitude of influence of each line on VPEL and on VPV are determined by the direction and magnitude of the separation between the upper pole of the spherical eye and the intersection of the great circle containing the line's image with the central vertical retinal meridian and with the midfrontal retinal meridian, respectively; (3) the influence of individual nonparallel lines is determined by a weighted average of the influences of individual sets of parallel lines; (4) a generalized version of the Great Circle Model is indicated in which extraretinal signals from head and eye are taken into account.

The impact of different dosing regimens of the aminoglycosides netilmicin and amikacin on vestibulotoxicity in the guinea pig.

The purpose of this study was to assess whether vestibulotoxicity caused by aminoglycoside antibiotics is influenced by the treatment schedule used: i.e., a single high dose given once daily (o.d.) vs multiple divided doses (tres in die, t.i.d.). Two groups of guinea pigs (5 animals/group) were injected intramuscularly for 21 days with either netilmicin or amikacin 150 mg/kg o.d., whereas other groups received each drug at 50 mg/kg t.i.d. at 8-h intervals. Amikacin was also given at 225 mg/kg o.d. and 75 mg/kg t.i.d. Vestibular functions were assessed by measuring vestibulo-ocular reflexes. Acoustic function was also evaluated by measuring Preyer's pinna reflex. Sensory epithelia of the inner ears were evaluated histologically under a scanning electron microscope. Netilmicin failed to affect either the vestibular or the acoustic apparatus in the animal groups receiving the two dosing regimens. Amikacin in a dose of 150 mg/kg per day induced an acoustic deficit which was more severe in the t.i.d. group. The higher dose of amikacin provoked significant lesions of acoustic and vestibular function, irrespective of the dosing regimen used. These data suggest that the o.d. dosing regimen of the aminoglycoside antibiotics might provide effective treatment for infectious diseases without enhancing the risk for vestibular and acoustic side effects.

The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate.

A controlled, double-blind study was carried out to determine whether nystagmus response to optokinetic or vestibular stimuli might be altered by some agent contained in powdered ginger root (Zingiber officinale). For comparative purposes, the test subjects were examined after medication with ginger root, placebo and with dimenhydrinate. Eye movements were recorded using standard ENG equipment and evaluation was performed by automatic nystagmus analysis. It could be demonstrated that the effect of ginger root did not differ from that found at baseline, or with placebo, i.e. it had no influence on the experimentally induced nystagmus. Dimenhydrinate, on the other hand, was found to cause a reduction in the nystagmus response to caloric, rotatory and optokinetic stimuli. From the present study it can be concluded that neither the vestibular nor the oculomotor system, both of which are of decisive importance in the occurrence of motion sickness, are influenced by ginger. A CNS mechanism, which is characteristic of the conventional anti-motion sickness drugs, can thus be excluded as regards ginger root. It is more likely that any reduction of motion-sickness symptoms derives from the influence of the ginger root agents on the gastric system.