Baclofen and velocity storage: a model of the effects of the drug on the vestibulo-ocular reflex in the rhesus monkey.
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 & 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 at 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 slowphase velocity were capable of functioning, at least intermittently, in the presence of the drug.(ABSTRACT TRUNCATED AT 400 WORDS)
Cohen
B
B
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029.
Helwig
D
D
Raphan
T
T
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D008253:Macaca mulatta; D008954:Models, Biological; D009760:Nystagmus, Physiologic / Q000187:drug effects; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects*; D012438:Saccades / Q000187:drug effects; D013997:Time Factors
D001418:Baclofen