Chronic all-trans retinoic acid administration induced hyperactivity of HPA axis and behavioral changes in young rats

Although clinical reports suggest a possible relationship between excess retinoids and the development of depression, the effect of retinoids on mood-related behavior remains controversial. Hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis plays a key role in the development of affective disorders. The present study aimed to elucidate the effect of retinoid on the activity of HPA axis in rat and whether this goes together with behavioral changes. All-trans retinoic acid (ATRA) was administered to juvenile male rats by daily intraperitoneal injection for 6 weeks. ATRA treatment increased basal serum corticosterone concentration as well as the thickness of adrenal cortex in young rat. Furthermore, the mRNA expression of corticotropin release factor (CRF) and retinoic acid receptor-α (RAR-α) in the hypothalamus was both markedly increased in ATRA-treated rats compared with vehicle. Some behavioral alterations were also observed. ATRA-treated rats showed anxiety-like behavior in elevated-plus maze and decreased spontaneous exploratory activities in novel open field. However, in the sucrose preference test chronic ATRA treatment did not modify behavior in the juvenile animals. Chronic administration of ATRA did not impair physical motor ability in either the prehensile traction or the beam balance/walk test. In conclusion, long-term ATRA administration resulted in hyperactivated HPA axis which was accompanied by several behavioral changes in young rat.