Researchers claim reproducible drug-related changes in OKR responses can be used with preclinical drug development tests.
Assessing changes in the eye movements of mice treated with CNS-active drugs could complement the existing range of in vivo tests to evaluate the therapeutic efficacy, pharmacokinetics, drug receptor interactions, and toxicity of a wide range of candidate drug compounds, researchers claim.
A team at Johns Hopkins University and the Howard Hughes Medical Institute compared eye-movement analysis with the commonly used rotarod test of motor coordination in mice treated with a number of different classes of CNS-active drugs. They found that treatment elicited distinctive and characteristic eye-movement responses that could be analyzed quantitatively to confirm drug dose, duration of action, receptor specificity, blood-brain barrier penetration, and agonist-antagonist interactions.
Reporting in The Journal of Clinical Investigation, Jeremy Nathans, Ph.D., Hugh Cahill, Ph.D., and Amir Rattner, Ph.D., state that changes in eye movements correctly indicated the therapeutic effect of antipsychotic drug treatment in a pharmacologic model of schizophrenia. They also identified disease in a mouse model of Huntington disease. Their paper is titled “Preclinical assessment of CNS drug action using eye movements in mice.”
Functional tests currently used to assess CNS drug action in rodents fall into four basic categories based on behavioral complexity: simple stimulus-response paradigms such as the startle reflex or paw withdrawal from a hot plate; stereotyped motor tasks such as balancing on a rotarod; complex innate behaviors such as circadian entrainment or open-field activity; and learned responses such as maze running.
While stimulus-response tests and stereotyped motor tasks can be carried out relatively quickly, complex innate behaviors and learned responses require more extensive monitoring or preliminary training trials. They are also associated with large trial-to-trial variability, the researchers note.
Eye movements in mice also represent a readily monitored behavior, which in nonfoveate mammals such as mice include an involuntary response to a moving stimulus known as the optokinetic reflex. This is characterized by a series of slow eye-tracking movements, interrupted at regular intervals by rapid resetting movements (saccades) in the opposite direction.
In theory, eye movements could represent a useful behavior of CNS activity, the team continues. Eye responses are rapid, don’t require training, and show little or no adaptation. And like electrocardiograms or electroencephalograms, eye movement recording lends itself to relatively simple and semi-automated analyses of peak size, shape, polarity, and spacing.
To assess the extent to which a variety of CNS-active drugs might affect eye movements in mice, Dr. Nathan’s team examined spontaneous and visual stimulus-induced eye movements after intraperiotneal injection of 48 drugs including antipsychotics, sedatives, antiseizure drugs, drugs of abuse such as cocaine, a CNS stimulate, and PTZ. Eye movements were analyzed using a custom-built eye-tracking apparatus.
In many cases treatment caused reproducible and quantifiable changes in ocular parameters such as pupil dilation and OKR in terms of frequency, duration, polarity, and shape, both spontaneously and in response to a moving visual stimulus. The eye movement effects include a slowing or complete suppression of the OKR, a shift in eye-movement direction, induction of spontaneous OKR-like movements in the absence of visual stimuli, clustering of the polarity or timing of OKR-like movements, and changes in the slope of the slow phase of the OKR-like movements.
The researchers found these characteristic drug-related changes could be used to evaluate blood-brain barrier penetration of drugs and even drug-receptor interaction, drug-drug interactions, and detect acute lead toxicity. Observations in a mouse model of schizophrenia further suggested that the suppression of phencyclidine-induced spontaneous eye movements could be used as a screening tool for antipsychotic drug candidates.
Separate studies in a mouse model of Huntington disease found that changes in spontaneous eye movements occurred at an age when animals with the disease were still too young to display any health-related symptoms or changes in rotarod performance. Interestingly, the researchers suggest, spontaneous eye movements in the Huntington disease model may represent the murine correlate of the saccade errors observed in human Huntington disease patients, and “presumably be used to follow disease progression or responses to treatment in presymptomatic Huntington disease animal models.”
Dr. Nathan’s team concludes that the studies “establish eye-movement analysis as a broadly useful tool for rapidly and quantitatively assessing the responses of mice to a wide variety of psychoactive compounds.” The results suggest that a wide range of neurotramsitter systems can influence eye movements in mice, including cholinergic, glutamatergic, aminergic, GABAergic, opioid, and cannabinoid systems. The authors admit that “at present, we do not know which drugs directly perturb eye-movement circuits and which act indirectly via changes in arousal, coordination, or higher mental states.”
Nevertheless, they state, “eye-movement analysis represents a potentially useful addition to the existing repertoire of behaviorally based drug assays. Since it is safe and noninvasive, it could be readily extended to larger mammals including humans.”