Baclofen and velocity storage: a model of the effects of the drug on the vestibulo‐ocular reflex in the rhesus monkey.

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Abstract
1. Baclofen had a characteristic effect on vestibular and optokinetic nystagmus in rhesus monkeys. Each aspect of nystagmus that is dependent on the velocity-storage mechanism in the vestibulo-ocular reflex (v.o.r.) was altered by the drug: (a) Baclofen reduced the dominant time constant of the v.o.r. in a dose-dependent manner up to 5 mg/kg, the highest dosage used. The alteration in v.o.r. time constant began within 15 min of injection, was maximal between 1 and 4 h, and lasted for 14-18 h. This effect mirrors changes in plasma levels of baclofen after oral doses in humans (Faigle, Keberle and Agen, 1980). (b) Slow-phase velocities of steady-state nystagmus induced by rotation about axes tilted from the vertical (off-vertical axis rotation, o.v.a.r.) were reduced after baclofen and could not be maintained at previous levels. (c) There was a dose-dependent decline in the steady-state gain of optokinetic nystagmus (o.k.n.), and the highest dosages little o.k.n. was induced. In parallel, the peak velocity and falling time constant of optokinetic after-nystagmus (o.k.a.n.) were reduced. Since baclofen is a GABA agonist, systems utilizing GABA and acting on GABAB receptors appear to produce inhibitory control of velocity storage. 2. The step gain of the v.o.r., measured at the beginning and end of constant-velocity rotation in darkness, was unaffected by baclofen, as were saccades, quick phases of nystagmus, and the ability to hold positions of fixation or to generate linear slow phases of nystagmus. This indicates that it is possible to use baclofen to manipulate the dominant time constant of the v.o.r. and of o.k.a.n. in relative isolation from effects on other oculomotor components. 3. Baclofen caused a dose-dependent reduction in the initial jump in eye velocity at the onset of o.k.n., suggesting that the initial jump is also under inhibitory control of GABAB receptors. However, there were still occasional slow phases with velocities up to 30-40 deg/s after baclofen, and animals were capable of visually suppressing the v.o.r. This indicates that pathways responsible for causing rapid changes in slow-phase velocity were capable of functioning, at least intermittently, in the presence of the drug. 4. The data were simulated by the model that predicts the v.o.r., o.k.n. and o.k.a.n. and visual-vestibular interactions (Raphan, Matsuo and Cohen, 1979; Waespe, Cohen and Raphan, 1983). The effect of baclofen was reproduced by shortening the falling time constant of the velocity-storage integrator, reducing the gain of the direct visual-oculomotor pathway and modifying the structure of the non-linearity that couples the visual system to the indirect pathway and the velocity-storage integrator. Alterations in the non-linearity explain why the time course of the slow rise in o.k.n. and the rising time constant of o.k.a.n. were longer at low or moderate doses of baclofen and shorter at high doses. 5. The functional effect of inhibition of velocity storage would be to reduce the responsiveness of compensatory oculomotor reflexes to low frequencies of head rotation and high rates of retinal slip. Similar effects are produced by habituation and during rapid discharge of activity from the v.o.r. by visual suppression or by tilting the head. GABA and GABAB receptors may also be utilized in mediating these processes.