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ToxSci Advance Access published online on July 20, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi262
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Published by Oxford University Press 2005.
Received June 14, 2005
Accepted July 8, 2005

Neurotoxicology

Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats

Sherry A. Ferguson 1*, F. Javier Cisneros 1, B. Gough 1, Joseph P. Hanig 2, and Kimberly J. Berry 1

1 Division of Neurotoxicology, National Center for Toxicological Research/FDA, 3900 NCTR Road, Jefferson, AR 72079
2 Center for Drug Evaluation Research/FDA, Silver Spring, MA

* To whom correspondence should be addressed.
Sherry A. Ferguson, E-mail: sferguson{at}nctr.fda.gov


  Abstract

Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at postnatal day 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations while neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at postnatal days 102-104 and 151-153 was not different from controls in any treated group; although all RA-treated groups had lower intakes. Swim speed in a water maze at posnatal day 180 was similar across groups indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at postnatal day 91 in 7.5 mg/kg treated males only, but was within control range at postnatal days 119, 147 and 175. Thus, at serum levels similar to those achieved by humans, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression.

Keywords: isotretinoin; 13-cis-retinoic acid; all-trans-retinoic acid depression; anhedonia; locomotor activity; forced swim test.
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