Chronic oral treatment with isotretinoin alters measures of activity but not anxiety in male and female rats

Abstract

Use of the anti-acne drug, Accutane® (ACC) (isotretinoin, 13-cis-retinoic acid), has been associated with neuropsychiatric events ranging from depression in animal models to depression and suicide ideation in humans. Our studies, however, have consistently indicated few effects on measures of depression in male and female rats. Still, the comorbidity of depression and anxiety suggests that anxiety assessments in ACC-treated rats could be informative. Such assessments must be balanced with measures of activity since drug-induced activity alterations may impact the expression of anxiety-like behaviors. Here, Sprague–Dawley rats ( n = 15/sex/dose) were gavaged daily with 0 (soy oil), 7.5, or 30 mg/kg/day ACC beginning on postnatal day (PND) 59. Blood ACC levels similar to humans taking recommended ACC doses are produced by 7.5 mg/kg/day. Short-term activity was assessed in open fields prior to ACC treatment (PND 51) and again at PNDs 129 and 164 and in a complex environment at PNDs 66 and PND 184. Long-term residential activity was measured in running wheels (PNDs 85–92) and figure 8 mazes (PNDs 99–106). Anxiety-like behavior was assessed via elevated plus maze (EPM) activity on PND 98 and in a black/white apparatus on PND 125. The typical sex differences in most behaviors were exhibited (i.e., increased EPM open arm entries and overall activity in most measures in females); however, there were no significant effects of ACC treatment on open field activity, complex environment activity, residential running wheel activity, or EPM activity. Residential figure 8 maze activity indicated that male and female rats treated with 30 mg/kg/day were less active on all nights ( p < 0.05) and females treated with 7.5 or 30 mg/kg/day were less active than same-sex controls on most days ( p < 0.05). Similarly, rats of both sexes treated with 30 mg/kg/day were significantly less active in the black/white apparatus ( p < 0.05), entering the darkened area less frequently ( p < 0.05), although duration in the darkened area did not differ. These data indicate that at blood levels typically achieved by humans (i.e., the 7.5 mg/kg group), there are no significant anxiogenic effects associated with ACC treatment. At higher ACC levels, there are mild effects on activity but these appear to be apparatus- and/or age-specific.