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Effects of baclofen on the angular vestibulo-ocular reflex

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Abstract

The purpose of this study was to determine the effect of baclofen, a GABAB agonist on the angular vestibulo-ocular reflex (aVOR). Model studies have shown that the aVOR comprises a “direct” pathway, which determines its high frequency gain g 1, and an indirect “velocity storage” pathway, which determines its low frequency characteristics. Velocity storage can be characterized by an integrator with a dominant time constant, T VOR, and a gain g 0 that couples afferent information from the semicircular canals to the integrator. Baclofen preferentially shortens the velocity storage time constant in monkeys, but its effect on T VOR, g 0, and g 1 in humans is unknown. Six subjects were tested after administration of a placebo or of 10, 20, or 30 mg of baclofen in a double-blind design. The aVOR was elicited in darkness with steps of rotation at 138°/s, and g 1, g 0, and T VOR were determined from model fits of the slow phase velocity of the per- and post-rotatory nystagmus. Baclofen significantly reduced both T VOR and g 0 at dosages of 20 and 30 mg, but had no effect on g 1. Small reductions in g 0 were associated with large reductions in vestibular output. Thus, baclofen does not affect the direct aVOR pathway in humans, but controls the low frequency aVOR in two ways: it limits the input to velocity storage and modulates its time constant. We speculate that pre-synaptic GABAB terminals in the vestibular nuclei are responsible for the control of the afferent input to velocity storage through g 0, while the post-synaptic GABAB terminals are responsible for altering the duration of activity that reflects the time constant. The lack of effect of baclofen on the aVOR gain suggests that only GABAA receptors are utilized in the direct aVOR pathway.

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References

  • Blanks RHI, Estes MS, Markham CH (1975) Physiologic characteristics of vestibular first order canal neurons in the cat II Response to constant angular acceleration. J Neurophysiol 38:1250–1268

    PubMed  CAS  Google Scholar 

  • Büttner U, Waespe W (1981) Vestibular nerve activity in the alert monkey during vestibular and optokinetic nystagmus. Exp Brain Res 41:310–315

    Article  PubMed  Google Scholar 

  • Clément G, Deguine O, Parant M, Costes-Salon MC, Vasseur-Clausen P, Pavy-LeTraon A (2001) Effects of cosmonaut vestibular training on vestibular function prior to spaceflight. Eur J Appl Physiol 85:539–545

    Article  PubMed  CAS  Google Scholar 

  • Cohen B, Suzuki JI (1963) Eye movement induced by ampullary nerve stimulation. Am J Physiol 204:347–351

    PubMed  CAS  Google Scholar 

  • Cohen B, Matsuo V, Raphan T (1977) Quantitative analysis of the velocity characteristics of optokinetic nystagmus and optokinetic after-nystagmus. J Physiol (Lond) 270:321–344

    CAS  Google Scholar 

  • Cohen B, Helwig D, Raphan T (1987) Baclofen and velocity storage: a model of the effects of the drug on the vestibulo-ocular reflex in the rhesus monkey. J Physiol 393:703–725

    PubMed  CAS  Google Scholar 

  • Cohen H, Cohen B, Raphan T, Waespe W (1992) Habituation and adaptation of the vestibulo-ocular reflex: a model of differential control by the vestibulo-cerebellum. Exp Brain Res 90:526–538

    Article  PubMed  CAS  Google Scholar 

  • Cohen B, Dai M, Raphan T (2003) The critical role of velocity storage in production of motion sickness. Ann NY Acad Sci 1004:359–376

    Article  PubMed  Google Scholar 

  • Correia MJ, Perachio AA, Dickman JD, Kozlovskaya IB, Sirota MG, Yakushin SB, Beloozerova IN (1992) Changes in monkey horizontal semicircular canal afferent responses after spaceflight. J Appl Physiol 73:112S–120S

    PubMed  CAS  Google Scholar 

  • Dai M, Klein A, Cohen B, Raphan T (1999) Model-based study of the human cupular time constant. J Vest Res 9:293–301

    CAS  Google Scholar 

  • Dai M, Kunin M, Raphan T, Cohen B (2003) The relation of motion sickness to the spatial-temporal properties of velocity storage. Exp Brain Res 151:173–189

    Article  PubMed  Google Scholar 

  • Faigle J, Keberle H, Degen P (1980) Chemistry and pharmacokinetics of beclofen. In: Feidman R, Young R, Koella W (eds) Spaslicity: disordered motor control. Year Book Medical Publishers, Chicago, pp 461–475

    Google Scholar 

  • Fernández C, Goldberg JM (1971) Physiology of peripheral neurons innervating semicircular canals of the squirrel monkey II Response to sinusoidal stimulation and dynamics of peripheral vestibular system. J Neurophysiol 34:661–675

    PubMed  Google Scholar 

  • Fromm GH, Terrence CF (1987) Comparison of l-baclofen and racemic baclofen in trigeminal neuralgia. Neurology 37:1725–1728

    PubMed  CAS  Google Scholar 

  • Gizzi MS, Harper HW (2003) Suppression of the human vestibulo-ocular reflex by visual fixation or forced convergence in the dark, with a model interpretation. Curr Eye Res 26:281–290

    Article  PubMed  Google Scholar 

  • Goldberg JM, Fernandez C (1971) Physiology of peripheral neurons innervating semicircular canals of the squirrel monkey I Resting discharge and response to angular accelerations. J Neurophysiol 34:635–660

    PubMed  CAS  Google Scholar 

  • Henn V (1981) Vestibular habituation in man and monkey during sinusoidal rotation. Ann NY Acad Sci 374:330–339

    Article  PubMed  Google Scholar 

  • Highstein SM, Rabbitt RD, Holstein GR, Boyle RD (2005) Determinants of spatial and temporal coding by semicircular canal afferents. J Neurophysiol 93:2359–2370

    Article  PubMed  Google Scholar 

  • Hirata Y, Highstein SM (2001) Acute adaptation of the vestibulo-ocular reflex: signal processing by floccular and ventral parafloccular Purkinje cells. J Neurophysiol 85:2267–2288

    PubMed  CAS  Google Scholar 

  • Holstein GR, Martinelli GP, Cohen B (1992a) l-Balcofen-sensitive GABAB binding sites in the medial vestibular nucleus localized by immunocytochemistry. Brain Res 581:175–180

    Article  CAS  Google Scholar 

  • Holstein GR, Martinelli GP, Cohen B (1992b) Immunocytochemical visualization of l-baclofen-sensitive GABAB binding sites in the medial vestibular nucleus. Ann NY Acad Sci 656:933–936

    Article  CAS  Google Scholar 

  • Holstein GR, Martinelli GP, Cohen B (1999a) Ultrastructure of GABA-immunoreactive vestibular commissural neurons related to velocity storage in the monkey. Neuroscience 93:171–181

    Article  CAS  Google Scholar 

  • Holstein GR, Martinelli GP, Cohen B (1999b) Ultrastructural features of non-commissural GABAergic neurons in the medial vestibular nucleus of the monkey. Neuroscience 93:183–193

    Article  CAS  Google Scholar 

  • Holstein GR, Martinelli GP, Henderson SC, Friedrich VL Jr, Rabbitt RD, Highstein SM (2004a) Gamma-aminobutyric acid is present in a spatially discrete subpopulation of hair cells in the crista ampullaris of the toadfish Opsanus tau. J Comp Neurol 471:1–10

    Article  CAS  Google Scholar 

  • Holstein GR, Rabbitt RD, Martinelli GP, Friedrich VL Jr, Boyle RD, Highstein SM (2004b) Convergence of excitatory and inhibitory hair cell transmitters shapes vestibular afferent responses. Proc Natl Acad Sci USA 101:15766–15771

    Article  CAS  Google Scholar 

  • Ito M (1984) The cerebellum and neural control. Raven Press, New York

    Google Scholar 

  • Lisberger SG, Pavelko TA (1988) Brain stem neurons in modified pathways for motor learning in the primate vestibulo-ocular reflex. Science 242:771–773

    Article  PubMed  CAS  Google Scholar 

  • Lisberger SG, Pavelko TA, Broussard DM (1994) Responses during eye movements of brain stem neurons that receive monosynaptic inhibition from the flocculus and ventral paraflocculus in monkeys. J Neurophysiol 72:909–927

    PubMed  CAS  Google Scholar 

  • Lorente de Nó R (1932) The regulation of eye positions and movements induced by the labyrinth. Laryngoscope 42:233–332

    Google Scholar 

  • Magnusson AK, Lindstrom S, Tham R (2000) GABA(B) receptors contribute to vestibular compensation after unilateral labyrinthectomy in pigmented rats. Exp Brain Res 134:32–41

    Article  PubMed  CAS  Google Scholar 

  • Magnusson AK, Ulfendahl M, Tham R (2002) Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABA(B) receptor function. Neuroscience 111:625–634

    Article  PubMed  CAS  Google Scholar 

  • Merfeld DM (1995) Modeling the vestibulo-ocular reflex of the squirrel monkey during eccentric rotation and roll tilt. Exp Brain Res 106:123–134

    Article  PubMed  CAS  Google Scholar 

  • Miles FA, Eighmy BB (1980) Long term adaptive changes in primate vestibuloocular reflex I Behavioral observations. J Neurophysiol 43:1406–1425

    PubMed  CAS  Google Scholar 

  • Miles FA, Fuller JH, Braitman DJ, Dow BM (1980) Long term adaptive changes in primate vestibulo-ocular reflex III Electrophysiological observations in flocculus of normal monkey. J Neurophysiol 43:1437–1476

    PubMed  CAS  Google Scholar 

  • Raphan T, Cohen B (1996) How does the vestibulo-ocular reflex work?. In: Baloh RW, Halmagyi GM (eds) Disorders of the vestibular system. Oxford University Press, New York, pp 20–47

    Google Scholar 

  • Raphan T, Cohen B (2002) The vestibulo-ocular reflex (VOR) in three dimensions. Exp Brain Res 145:1–27

    Article  PubMed  Google Scholar 

  • Raphan T, Matsuo V, Cohen B (1977) A velocity storage mechanism responsible for optokinetic nystagmus (OKN), optokinetic after-nystagmus (OKAN) and vestibular nystagmus. In: Baker R, Berthoz A (eds) In control of gaze by brain stem neurons. Elsevier/North Holland, Amsterdam, pp 37–47

    Google Scholar 

  • Raphan T, Matsuo V, Cohen B (1979) Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp Brain Res 35:229–248

    Article  PubMed  CAS  Google Scholar 

  • Reisine H, Raphan T (1992) Neural basis for eye velocity generation in the vestibular nuclei during off-vertical axis rotation. Exp Brain Res 92:209–226

    Article  PubMed  CAS  Google Scholar 

  • Robinson D (1977) Vestibular and optokinetic symbiosis: an example of explaining by modeling. In: Baker R, Berthoz A (eds) Control of gaze by brain stem neurons. Elsevier/North Holland, Amsterdam, pp 49–58

    Google Scholar 

  • Singleton GT (1967) Relationships of the cerebellar nodulus to vestibular function: a study of the effects of nodulectomy on habituation. Laryngoscope 77:1579–1620

    Article  PubMed  CAS  Google Scholar 

  • Solomon D, Cohen B (1994) Stimulation of the nodulus and uvula discharges velocity storage in the vestibulo-ocular reflex. Exp Brain Res 102:57–68

    Article  PubMed  CAS  Google Scholar 

  • Szczepaniak WS, Moller AR (1995) Effects of l-baclofen and d-baclofen on the auditory system: a study of click-evoked potentials from the inferior colliculus in the rat. Ann Otol Rhinol Laryngol 104:399–404

    PubMed  CAS  Google Scholar 

  • Waespe W, Henn V (1977a) Neuronal activity in the vestibular nuclei of the alert monkey during vestibular and optokinetic stimulation. Exp Brain Res 27:523–538

    Article  CAS  Google Scholar 

  • Waespe W, Henn V (1977b) Vestibular nuclei activity during optokinetic after-nystagmus (OKAN) in the alert monkey. Exp Brain Res 30:323–330

    Article  CAS  Google Scholar 

  • Wilson VJ, Melvill-Jones G (1979) Mammalian vestibular physiology. Plenum Press, New York

    Google Scholar 

  • Yakushin SB, Raphan T, Cohen B (2005) Spatial properties of central vestibular neurons. J Neurophysiol DOI: 10.1152/jn 00459-2005

  • Yokota JI, Reisine H, Cohen B (1992) Nystagmus induced by electrical microstimulation of the vestibular and prepositus hypoglossi nuclei in the monkey. Exp Brain Res 92:123–138

    Article  PubMed  CAS  Google Scholar 

  • Zee DS, Yamazaki A, Butler PH, Gucer G (1981) Effects of ablation of flocculus and paraflocculus on eye movements in primate. J Neurophysiol 46:878–899

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by NSBRI NA00406, DC005204, and DC05222.

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Authors and Affiliations

  1. Department of Neurology, Mount Sinai School of Medicine, 1 East 100th Street, Box 1135, New York, NY, 10029-6574, USA

    Mingjia Dai & Bernard Cohen

  2. Department of Computer and Information Science, Brooklyn College, City University of New York, Brooklyn, NY, 11210, USA

    Theodore Raphan

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  1. Mingjia Dai
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  2. Theodore Raphan
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  3. Bernard Cohen
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Correspondence to Mingjia Dai.

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Dai, M., Raphan, T. & Cohen, B. Effects of baclofen on the angular vestibulo-ocular reflex. Exp Brain Res 171, 262–271 (2006). https://doi.org/10.1007/s00221-005-0264-y

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