of dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA) and brain derived neurotrophic factor (BDNF) and activity of monoamine oxidase (MAO) in the hippocampus and frontal cortex of adult male albino rats. The cortisol level was determined in serum. Gene expression of mu (MORs) and Kappa (KORs) opioid receptors genes and DNA damage were measured in the hippocampus-frontal cortex rat brains. The results show that administration of isotretinoin or clonidine caused an increase in DA, NE, 5-HIAA and BDNF concentrations, and a decrease in MAO enzyme activity in both the hippocampus and frontal cortex. In the hippocampus and frontal cortex, the 5-HT concentration increased significantly following clonidine treatment but not significantly changed after isotretinoin treatment. The level of serum cortisol increased following treatment with either isotretinoin or clonidine. Significant increases in MORs and KORs genes expression levels as well as in DNA damage of hippocampusfrontal cortex brain areas were also seen in isotretinoin or clonidine-treated rats compared with control rats. These results provide evidence that the depressive-like effects induced by isotretinoin or clonidine are exerted through alteration in monoamines, brain derived neurotrophic factor and cortisol levels as well as in opioid receptors gene expression.