We compare the effects of psychoactive drugs such as morphine and amphetamine on the synaptic organization of neurons in the orbital frontal (OFC) and medial frontal (mPFC) regions in the rat. Both regions are altered chronically by exposure to intermittent doses of either drug but the effects are area-dependent. For example, whereas morphine produces increased spine density in OFC but decreased spine density in mPFC. The differential response of the OFC and mPFC to drugs is paralleled by an areal-dependent effect of gonadal hormones on these regions as well: males have greater dendritic arborization in the mPFC whereas females have a greater arborization in the OFC. We also compared the effects of neonatal injury to the OFC and mPFC on cognitive, motor, and social behaviors as well as on the anatomical organization of the remaining brain. Again, there were differential effects of the treatments to the OFC and mPFC. Neonatal OFC lesions allowed virtually complete functional recovery of cognitive and motor behaviors, which was correlated with mild abnormalities in cerebral development compared to the more severe deficits and morphological sequelea following mPFC lesions at the same ages. One exception was the effect of OFC on social behavior, which was severe regardless of whether the injury was in infancy or adulthood. It is proposed that both drug-induced and developmental abnormalities in the integrity of OFC neurons may lead to deficits in social behavior or other behavioral pathologies, possibly including depression.