Preclinical assessment of CNS drug action using eye movements in mice
Hugh Cahill, Amir Rattner, Jeremy Nathans
Hugh Cahill, Amir Rattner, Jeremy Nathans
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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 7

Strain differences, receptor specificity, and agonist-antagonist interactions analyzed by eye-movement analysis.

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Strain differences, receptor specificity, and agonist-antagonist interac...
(A) Morphine (200 mg/kg, oral delivery) eliminates the OKR in C57BL/6J mice but not in 129SvEv mice. Scale bar: 0.5 mm. (B) OKR suppression by 200 mg/kg morphine is eliminated in Oprm1–/– mice but not Oprm1+/+ littermates in a C57BL/6J background. (C) Quantification of the effects of 200 mg/kg morphine on the OKR, pupil dilation, and rotarod performance in Oprm1–/– and Oprm1+/+ littermates. (D) Quantification of OKR suppression and pupil dilation in C57BL/6J and 129SvEv mice in response to 200 mg/kg morphine. (E) Naloxone blockade of morphine-induced suppression of the OKR. Time line of drug administration and OKR recordings (top). Representative OKR traces (bottom left). Quantification of ETM30 (bottom right). i.p. naloxone administered at 10 mg/kg 10 minutes before 200 mg/kg oral morphine blocked morphine-induced OKR suppression. Data in C and E are averages from 3 Oprm1–/– and Oprm1+/+ mice. Data in D are averages from 6 C57BL/6J and 4 129SvEv mice. Scale bar: 1 mm. Data are presented as the mean ± standard deviation.