Neurotransmitter Drugs that Affect Vertebrate Eye Movements
Application of pharmacological agents within the visual system has been used both to treat ocular disease and to investigate normal mechanisms of visual function and neural development. This chapter will describe experiments that use GABAergic and glutamatergic drug application to understand the underlying mechanisms through which the visual system influences oculomotor behaviors. This discussion will describe some results using intracranial drug injection but will mainly focus on drug effects following intravitreal injections.
Because there are several oculomotor behaviors and several parallel pathways by which visual information streams from the retina through the brain, let us generalize somewhat. The visual cortex is involved in perception of color and form, although the cortex also computes the position and direction of visual stimuli. Stimulus position is required by the superior colliculus for the control of saccades, and stimulus direction and speed are used by brainstem structures (the accessory optic system and pretectum) to stabilize retinal images (minimize retinal slip). A constant retinal slip results in ocular nystagmus, with the fast phase eye movements recentering the gaze to allow for more slow phase movement.
Thus, the eye movements of animals trained to detect a target may be modified by drugs that affect retino-geniculo-cortical visual pathways. Saccades to certain positions in visual space may be influenced by chemical agents that alter the output of the superior colliculus. Finally, nystagmus may result from drugs that upset the processing of the retinal slip velocity of the global visual image.
Irrespective of the oculomotor behavior, these experiments use a common rationale: mimic a visual neuron’s neurotransmitter release or block its transmitter’s effect on postsynaptic cells. The protocols for these experiments are also similar. First, a pharmacological agent is chosen that has a known effect on a specific cell surface synaptic receptor of a specific neuron type that is near the site of drug application. Second, a dose is selected such that the cell’s response will be modulated without nonspecific effects on adjacent nerve cells or axons. Third, prior to drug application, normal oculomotor behavior is characterized by measuring eye movements that occur spontaneously, reflexively, or in response to training. Fourth, following these control measurements, the drug is administered and eye movements are again measured to detect drug-related changes. Fifth, oculomotor behavior is monitored to determine the time course of recovery from the drug’s effect.
As with the analysis of any behavioral effect of a pharmacological manipulation, many difficulties arise in interpreting these results. First, the effects of the drug must be distinguished from any effects of drug administration (e.g., transient effects of the anesthesia, ocular irritation caused by puncture of the globe by a hypodermic needle, changes in the intraocular pressure, changes in the ocular optics). Second, the dose should be minimized to be selective for the intended synaptic receptors without affecting neurons elsewhere via drug diffusion away from the injection site. Third, for intraocular drug injections, it should be confirmed that the change in retinal output stems from changes at retinal synapses and not from changes in accommodation, pupilloconstriction, or the motility of the extraocular muscles. Fourth, the interpretation should consider all possible pathways through which a change in synaptic transmission could be relayed by the parallel pathways in the visual system in order to affect the oculomotor response.
Such an analysis is often confounded by the closed-loop nature of visually driven oculomotor responses. Changes in visual processing that lead to changes in oculomotor responses will ultimately cause changes in the visual stimulus position as the retinal image is shifted by an eye movement. There is also the possibility of direct oculomotor feedback onto ganglion cells via centrifugal inputs to the retina (Marchiafava, 1976; Martin et al., 1990).
Of all these considerations, perhaps the greatest concern is the specificity of the pharmacological agents. It is for this reason that the analysis of the effects of intravitreal drug injections on eye movements is often complemented by electrophysiology of appropriate neural structures. These electrophysiological and behavioral results, as well as related anatomical and pharmacological evidence, can then be used to postulate the underlying mechanisms of visual system input to oculomotor control.
KeywordsSuperior Colliculus Intravitreal Injection Optokinetic Nystagmus Spontaneous Nystagmus Velocity Storage
Unable to display preview. Download preview PDF.
- Ariel M (1989): Analysis of vertebrate eye movements following intravitreal drug injections: 3. Spontaneous nystagmus is modulated by the GABAa receptor. J Neurophysiol 62:469–479.Google Scholar
- Ariel M (1991): Analysis of vertebrate eye movements following intravitreal drug injections: 4. Drug-induced eye movements are unyoked in the turtle. J Neurophysiol 65:1003–1009.Google Scholar
- Ariel M, Adolph AR (1985): Neurotransmitter inputs to directionally sensitive turtle retinal ganglion cells. J Neurophysiol 54:1123–1143.Google Scholar
- Ariel M, Robinson FR, Knapp AG (1988): Analysis of vertebrate eye movements following intravitreal drug injections: 2. Spontaneous nystagmus induced by picrotoxin is mediated subcortically. J Neurophysiol 60:1022–1035.Google Scholar
- Ariel M, Tusa RJ (1992): Spontaneous nystagmus and gaze-holding ability in monkeys following intravitreal picrotoxin injections. J Neurophysiol 67:1124–1132.Google Scholar
- Bonaventure N, Wioland N, Bigenwald J (1983): Involvement of GABAergic mechanisms in the optokinetic nystagmus of the frog. Exp Brain Res 50:433–441.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.Google Scholar
- Dacheux RF, Raviola E (1986): The rod pathway in the rabbit retina: A depolarizing bipolar and amacrine cell. J Neurosci 6:331–345.Google Scholar
- Hikosaka O, Wurtz RH (1985a): Modification of saccadic eye movements by GABArelated substances: 1. Effect of muscimol and bicuculline in monkey superior colliculus. J Neurophysiol 53:266–289.Google Scholar
- Hikosaka O, Wurtz RH (1985b): Modification of saccadic eye movements by GABArelated substances: 2.Effects of muscimol in monkey substantia nigra pars reticulata. J Neurophysiol 53:292–307.Google Scholar
- Hoffmann KP (1986): Visual inputs relevant for the optokinetic nystagmus in mammals. In: Progress in Brain Research, Freund HJ, Buttner U, Cohen B, Noth J, eds. Amsterdam: Elsevier.Google Scholar
- Horton JC, Sherk H (1984): Receptive field properties in the cat’s lateral geniculate nucleus in the absence of ON-center retinal input. J Neurosci 4:374–380.Google Scholar
- Knapp AG, Ariel M (1984): Selective blockade of retinal ON channel eliminates horizontal optokinetic nystagmus in rabbits. Invest Ophthalmol Vis Sci (Suppl) 25:229.Google Scholar
- Knapp AG, Ariel M, Robinson FR (1988): Analysis of vertebrate eye movements following intravitreal drug injections: 1. Blockade of retina ON-cells by 2-amino-4-phos-phonobutyrate eliminates optokinetic nystagmus. J Neurophysiol 60:1010–1021.Google Scholar
- Knapp AG, Mistler LA (1983): Response properties of cells in rabbit’s lateral geniculate nucleus during reversible blockade of retinal ON-center channel. J Neurophysiol 50:1236–1245.Google Scholar
- Marchiafava PL (1976): Centrifugal actions on amacrine and ganglion cells in the retina of the turtle. J Physiol 255:137–155.Google Scholar
- Martin G, Letelier JC, Wallman J (1990): Saccade-related responses of centrifugal neurons projecting to the chicken retina. Exp Brain Res 82:263–270.Google Scholar
- Müller F, Wassle H, Voigt T (1988): Pharmacological modulation of the rod pathway in the cat retina. J Neurophysiol 59:1657–1672.Google Scholar
- Mustari MJ, Fuchs AF (1990): Discharge patterns of neurons in the pretectal nucleus of the optic tract (NOT) in the behaving primate. J Neurophysiol 64:77–90.Google Scholar
- Reisine H, Cohen B (1990): Nucleus of the optic tract (NOT): Effect of muscimol on generation of optokinetic nystagmus and suppression and habituation of vestibular nystagmus. Soc Neurosci Abstr 16(2): 968.Google Scholar
- Rosenberg AF, Ariel M (1991): Electrophysiological evidence for a direct projection of direction-sensitive retinal ganglion cells to the turtle’s accessory optic system. J Neurophysiol 65:1002–1033.Google Scholar
- Schiff D, Cohen B, Raphan T (1988): Nystagmus induced by stimulation of the nucleus of the optic tract in the monkey. Exp Brain Res 70:1–14.Google Scholar