The prefrontal cortex (PFC) efferent projections to limbic areas facilitate a top-down control on the execution of goal-directed behaviours. The PFC sends glutamatergic outputs to limbic areas such as the hippocampus and amygdala which in turn modulate the activity of the nucleus accumbens (NAc). Dopamine and acetylcholine neurons in the brainstem and basal forebrain/septal areas, which send outputs to NAc, hippocampus and amygdala, are also regulated by PFC glutamatergic projections, and seem to be of special relevance in modulating motor, emotional and mnemonic functions. Both the physiological and pathological changes in the PFC influence the activity of these limbic areas and the corresponding final-guided behaviours. We revise our most recent studies on PFC-NAc interactions focussed on the role of dopamine and glutamate receptors in the PFC. Specifically, by performing microinjections/microdialysis studies we found that the activation of D2 dopamine receptors and the blockade of glutamate NMDA receptors in the PFC change the release of dopamine and acetylcholine in the NAc. We suggest the possibility that dopamine and glutamate receptors in the PFC could change the activity of dopamine and acetylcholine function in the hippocampus and amygdala. Finally, it is speculated that changes in the function of the PFC, associated with psychiatric disorders or due to environmental-dependent plasticity, can change PFC-limbic system interactions.