Previous experimental studies have shown that the prefrontal cortex (PFC) regulates the activity of the nucleus accumbens (NAc), and in particular the release of dopamine in this area of the brain. In the present report we review recent microinjections/microdialysis studies from our laboratory on the effects of stimulation/blockade of dopamine and glutamate receptors in the PFC that modulate dopamine, and also acetylcholine release in the NAc. Stimulation of prefrontal D2 dopamine receptors, but not group I mGlu glutamate receptors, reduces the release of dopamine and acetylcholine in the NAc and spontaneous motor activity. This inhibitory role of prefrontal D2 receptors is not changed by acute systemic injections of the NMDA antagonist phencyclidine. On the other hand, the blockade of NMDA receptors in the PFC increases the release of dopamine and acetylcholine in the NAc as well as motor activity which suggests that the hypofunction of prefrontal NMDA receptors is able to produce the neurochemical and behavioural changes associated with a dysfunction of the corticolimbic circuit. We suggest here that dopamine and glutamate receptors are, in part, segregated in specific cellular circuits in the PFC. Thus, the stimulation/blockade of these receptors would have a different net impact on PFC output projections to regulate dopamine and acetylcholine release in the NAc and in guided behaviour. Finally, it is speculated that environmental enrichment might produce plastic changes that modify the functional interaction between the PFC and the NAc in both physiological and pathological conditions.