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.

Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats.

Male and female Sprague-Dawley rats were orally gavaged with 13-cis-retinoic acid (7.5 or 15 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg) for 7 consecutive days. Blood was collected out to 8 hr after the last gavage on day 7. HPLC serum concentrations of 13-cis-retinoic acid, all-trans-retinoic acid, and 13-cis-4-oxo-retinoic acid were subjected to model independent pharmacokinetic analyses. Peak serum levels of 563 to 1640 ng/ml were observed for rats treated with 13-cis-retinoic acid at 1.5-2 hr after gavage. Peak serum levels of 183 to 267 ng/ml at 1.5 hr after gavage were observed for all-trans-retinoic acids. The elimination half-life of 13-cis-retinoic acid was about 1.5 hr while the elimination half-life of all-trans-retinoic acid was slightly longer. There were no sex differences for any parameter. Serum levels resulting from the 7.5 mg/kg 13-cis-retinoic acid were similar to those of human Accutane users.

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

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 (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 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 PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, 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.

Four weeks of oral isotretinoin treatment causes few signs of general toxicity in male and female Sprague-Dawley rats.

Despite widespread use of isotretinoin for its anti-acne effects and its current evaluation in clinical trials as a cancer treatment, little is known about its general toxicity in adult nonpregnant animals, particularly after oral administration which mimics the human route. Here, adult male and female Sprague-Dawley rats were gavaged daily with 0 (soy oil), 7.5, or 15 mg/kg isotretinoin for 28 days during which time body weight, food/water intake, and estrous phase were measured. At sacrifice, organ weights were collected and concentrations of dopamine (DA), serotonin and metabolites were measured in frontal cortex, striatum, hippocampus, and diencephalon. Food intake was mildly decreased in both treated groups (approximately 15% in males and 7% in females); however, body weight and water consumption were unaffected. The estrous cycle appeared slightly affected (i.e., lengthened by 15 mg/kg, and both treated groups appeared to have less time in diestrus and more time in estrus). Kidney/body weight ratio was decreased by 7.5 and 15 mg/kg isotretinoin and spleen/body weight ratio was increased in the 7.5 mg/kg group. Males of the 7.5 mg/kg group exhibited significantly higher gonad/body weight ratios than did same-sex controls. Concentrations of monoamine and metabolites in the frontal cortex and diencephalon were unaffected. Nor were striatal DA and DOPAC concentrations affected; however, there were isolated effects on striatal HVA and 5-HIAA. Hippocampal DA concentrations were marginally increased. These data indicate mild effects resulting from oral isotretinoin treatment at doses which likely produce serum levels within the range of humans.

5-AZA-2'-deoxycytidine (5-AZA-CdR): a demethylating agent affecting development and reproductive capacity.

The objective was to evaluate the effects of 5-AZA-2'-deoxycytidine (5-AZA-CdR) on postnatal development and reproductive capacity. Pregnant mice were administered 1 mg kg-1 5-AZA-CdR at gestation day 10. The body weights of F1 control and treated (in uterine-exposed) pups were recorded. To evaluate the reproductive capacity, 5-AZA-CdR F1 males and females were mated with control mice. The presence of plugs and the number of pregnancies were recorded. The 5-AZA-CdR F1 male mice were killed. Total body, testes and epididymis weights were recorded. Spermatid head counting, histological analyses and serum testosterone levels were performed. Body weights of 5-AZA-CdR F1 mice were statistically lower than controls (P < 0.01), with the females more strongly affected (P < 0.05). Male mating capacity appeared to be more adversely affected. Mating of 5-AZA-CdR F1 males with control females resulted in a lower pregnancy rate compared with control mating groups (P < 0.01). Gross testicular and epididymis weights were lower in 5-AZA-CdR F1 mice (P < 0.01). However, testicular and epididymis weights in these mice were higher than controls when correlated to body weight (P < 0.01). In 5-AZA-CdR F1 male mice, all measured reproductive parameters, including total number of spermatid heads per testis, are significantly lower (P < 0.01) than the controls except for the number of spermatid heads per milligram of testis.