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 5

Quantifying the increase in spontaneous eye movements induced by cocaine.

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Quantifying the increase in spontaneous eye movements induced by cocaine...
(A) Representative 30-second records of spontaneous eye movements (i.e., with no moving visual stimulus) recorded prior to and after an i.p. injection of 20 mg/kg cocaine. The box-car shape of the eye movements is retained, but the frequency of movements increases after cocaine administration. (B) Histograms for individual mice showing horizontal eye position differences between time points separated by 2 seconds (Xt–Xt–2) and sampled at 16.7-millisecond intervals. Data are the Xt–Xt–2 averages for the 15 minutes immediately after i.p. injection of PBS (black) or cocaine (red) at the indicated doses. n indicates the number of mice averaged per condition. Horizontal eye position (x) is plotted in “image units,” a distances measure in the video image. (C) 50th percentile cutoff value for the Xt–Xt–2 distributions for each mouse. Horizontal bars represent the mean. Individual symbols represent individual mice. (D) Time course of spontaneous eye movements plotted for each 30-second recording interval; the interleaved 30-second intervals with moving black and white stripes were omitted from the analysis. Spontaneous eye movements are quantified as in C. Individual symbols represent individual mice. Data are presented as the mean ± standard deviation.