BACLOFEN AND VELOCITY STORAGE - A MODEL OF THE EFFECTS OF THE DRUG ON THE VESTIBULOOCULAR REFLEX IN THE RHESUS-MONKEY
BACLOFEN AND VELOCITY STORAGE - A MODEL OF THE EFFECTS OF THE DRUG ON THE VESTIBULOOCULAR REFLEX IN THE RHESUS-MONKEY
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DOI：
10.1113/jphysiol.1987.sp016849
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发表时间：
1987-12-01
影响因子：
5.5
通讯作者：
RAPHAN, T
中科院分区：
文献类型：
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作者：
COHEN, B;HELWIG, D;RAPHAN, T
1.巴氯芬对恒河猴的前庭和视动性眼球震颤具有特征性作用。依赖于前庭眼反射（v.o.r.）中速度储存机制的眼球震颤的每个方面都是由眼内反射（v.o.r.）（a）巴氯芬降低了v.o.r.的主要时间常数。以剂量依赖性方式，最高剂量为5 mg/kg。v.o.r.的改变。时间常数在注射后15 min内开始，在1 - 4 h之间最大，持续14-18 h。该效应反映了人类经口给药后巴氯芬血浆水平的变化（Faigle、Keberle和阿根，1980）。(b)围绕倾斜于垂直方向的轴旋转（偏离垂直轴旋转，o.v.a.r.）引起的稳态眼球震颤的慢相速度在巴氯芬后减少，不能维持在以前的水平。(c)视动性眼震（o.k.n.）的稳态增益呈剂量依赖性下降，而最高剂量的小O.K.N.被诱导。同时，测量了视动性后眼球震颤（o.k.a.n.）减少了。由于巴氯芬是GABA激动剂，利用GABA和作用于GABAB受体的系统似乎产生对速度储存的抑制性控制。2. v.o.r.的阶跃增益，在黑暗中恒速旋转的开始和结束时测量，不受巴氯芬的影响，扫视、眼球震颤的快速相位以及保持固定位置或产生眼球震颤的线性缓慢相位的能力也不受巴氯芬的影响。这表明巴氯芬有可能操纵v.o.r.的主导时间常数。和O.K.A.N.相对独立于对其他眼内成分的影响。3.巴氯芬在O.K.N.开始时引起眼速度初始跳跃的剂量依赖性降低，提示初始跳跃也受GABAB受体的抑制控制。然而，巴氯芬给药后仍偶尔出现速度高达30-40 deg/s的慢相，动物能够视觉抑制v.o.r.。这表明，在药物存在下，负责引起慢相速度快速变化的途径能够发挥作用，至少是间歇性的。4.数据是通过预测v.o.r.的模型模拟的，好的好的和视觉-前庭相互作用（Raphan，Matsuo和Cohen，1979; Waespe，Cohen和Raphan，1983）。巴氯芬的效果是通过缩短速度存储积分器的下降时间常数，降低直接视觉-眼视通路的增益和修改将视觉系统耦合到间接通路和速度存储积分器的非线性结构来再现的。非线性的变化解释了为什么o.k.n.缓慢上升的时间过程。和O.k.a.n.的上升时间常数。在低剂量或中等剂量的巴氯芬时较长，在高剂量时较短。5.抑制速度储存的功能效应将是降低补偿性眼反射对低频率头部旋转和高速率视网膜滑动的反应性。习惯化和从v.o.r.快速释放活动时也会产生类似的效果。通过视觉抑制或通过倾斜头部。GABA和GABAB受体也可用于介导这些过程。
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.