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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 Article has an altmetric score of 6

Preclinical assessment of CNS drug action using eye movements in mice

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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 1

Survey of drug effects on the OKR.

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Survey of drug effects on the OKR.
Drugs were delivered by i.p. injectio...
Drugs were delivered by i.p. injection at the doses listed in Supplemental Tables 1 and 2. (A–C) Medicinal and miscellaneous psychoactive compounds. (A) Representative 90-second OKR responses to 30 seconds of rotating black and white stripes, preceded and followed by 30 seconds of a uniform gray. Visual stimuli are represented schematically at the top of each panel. Scale bar: 0.5 mm. (B) Four-minute OKR record with continuously rotating black and white stripes after i.p. injection of 2 g/kg ethanol as a 25% ethanol solution in PBS, i.e., equivalent to a blood alcohol level of approximately 0.2%. Scale bar: 1 mm. (C) Quantification of ETM30 during the moving stimulus interval. (D–F) Drugs of abuse and related compounds. (D and E) Representative 90-second OKR records and their quantification, as described for A and C. Scale bar: 0.5 mm. (F) Rotarod performance. For this and all other rotarod experiments, mice were given the same drug doses as shown for the OKR. In most cases, mice were tested immediately after OKR testing. Rotarod performance is quantified as the time to fall off a cylinder rotating at 7 revolutions per minute. Trials were terminated at 60 seconds. Between 2 and 7 mice were tested per drug. Data are presented as the mean ± standard deviation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 3 patents
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