Oral treatment with ACCUTANE does not increase measures of anhedonia or depression in rats.
Reports of depression and/or suicide with ACCUTANE (13-cis-retinoic acid (13-cis-RA)) use prompted studies in a rodent model to ascertain its potential effects. Previously, there were no effects on measures of anhedonia (intake of a saccharin-flavored solution) and depression (forced swim test (FST) behaviors) in rats treated with 7.5 or 22.5 mg/kg 13-cis-RA [S.A. Ferguson, F.J. Cisneros, B. Gough, J.P. Hanig, K.J. Berry, Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats, Toxicol. Sci. 87 (2005) 451-459.]. Here, dose and temporal thresholds were investigated by increasing the maximum 13-cis-RA dose to 30 mg/kg, extending treatment duration, and measuring behaviors repeatedly. Beginning on post-natal day 59, male and female Sprague-Dawley rats were gavaged with soybean oil, 7.5 or 30 mg/kg/day of 13-cis-RA for approximately 19 weeks. FST behaviors were measured after 24, 82, and 131 treatment days and saccharin intake (0.03% solution) was measured at baseline and after 14, 35, 56, and 112 treatment days. Body weight and food intake were not altered by treatment. FST durations of swim, climb/struggle, and immobility were unaffected by 13-cis-RA at any time during treatment. More males than females required "rescue" in the FST but there was no treatment effect on number of rats requiring early removal. 13-cis-RA treatment had no effects on saccharin intake at any time. Given that the 7.5 mg/kg dose produces serum levels which parallel those of humans [S.A. Ferguson, P.H. Siitonen, F.J. Cisneros, B. Gough, J.F. Young, Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats, Basic Clin. Pharmacol. Toxicol 98 (2006) 582-587.], these results are quite relevant. Combined with previous results, these results provide further evidence that 13-cis-RA does not produce behavioral alterations indicative of depression in rats.
Ferguson
Sherry A
SA
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079 USA. Sherry.Ferguson@fda.hhs.gov
Cisneros
F Javier
FJ
Hanig
Joseph P
JP
Berry
Kimberly J
KJ
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005518:Food Preferences / Q000187:drug effects*; D015474:Isotretinoin / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013550:Swimming; D013723:Teratogens; D013997:Time Factors
D013723:Teratogens; D015474:Isotretinoin