Preclinical assessment of CNS drug action using eye movements in mice
Hugh Cahill, … , Amir Rattner, Jeremy Nathans
Hugh Cahill, … , Amir Rattner, Jeremy Nathans
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3528-3541. https://doi.org/10.1172/JCI45557.
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Technical Advance Neuroscience

Preclinical assessment of CNS drug action using eye movements in mice

Abstract

The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development.

Authors

Hugh Cahill, Amir Rattner, Jeremy Nathans

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Figure 2

Quantifying the dose response and time course of drug action.

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Quantifying the dose response and time course of drug action. OKR and ro...
OKR and rotarod performance at the indicated times after a single i.p. injection of 85 mg/kg phenytoin or approximately 30–60 minutes after the indicated doses of gabapentin, diazepam, or zolpidem. Top panels show representative 90-second OKR records; center panels quantify the ETM30 during the rotating visual stimulus interval; and bottom panels quantify rotarod performance, as described in Figure 1. For phenytoin, boxed regions from the preinjection and 24-hour postinjection OKR records are enlarged 4 fold and shown as insets. The number of mice tested per time point or drug concentration is as follows: phenytoin, 3–6 mice; gabapentin, 3 mice; diazepam, 3–5 mice; and zolpidem, 3 mice. In the histograms, each ETM30 and rotarod data point was compared by t test to the preinjection control; only those comparisons with P < 0.05 are shown. P values of less than 10–4 are rounded to the nearest factor of 10. Scale bar: 0.5 mm. Data are presented as the mean ± standard deviation.