Neurotransmitter Drugs that Affect Vertebrate Eye Movements

Overview

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.