We recently investigated the effects of stress on synaptic plasticity in the prefrontal cortex, namely the prelimbic area or the apparent homologue of the primate subgenual prefrontal cortex in humans where most of the hippocampal terminal fields are localized. Exposure to an acute stress causes a remarkable and long-lasting inhibition of long term potentiation (LTP) in the frontal cortex evoked by stimulation of hippocampal outflow and this impairment is prevented by the glucocorticoid receptor antagonist mifepristone. Thus, the frontal cortex is also a target for glucocorticoids involved in the stress response. Current data show that antidepressants of various types, i.e., tianeptine and fluoxetine, at doses normally used in antidepressant testing, restore LTP impaired by prior acute stress. Interestingly, clozapine administered in a similar way after stress rapidly reverses the stress-induced impairment of LTP at doses which do not affect LTP alone. This stress paradigm highlights comorbidity for both etiology and treatment of psychiatric disorders like depression and schizophrenia. Restoring appropriate cognitive functions in circuits associated with dysfunctions in coping with stress may be proposed as a new systems-level approach to drug discovery and development. We are presently investigating the involvement of signalling molecules in producing these plastic changes.