Preferential activation of cortical dopamine neurotransmission by clozapine: functional significance

Dopamine projections to the prefrontal cortex are thought to be essential for the proper functioning of this region and are proposed to be involved in negative (deficit) symptomatology of schizophrenia. Our studies in the rodent indicate that clozapine, the most effective antipsychotic drug for the treatment of negative symptoms, causes an increase in the basal output of dopamine neurons projecting to the prefrontal cortex. This finding is in contrast to the effect of clozapine in the basal ganglia and the effect of typical antipsychotic drugs such as haloperidol in the prefrontal cortex. The ability of clozapine to increase dopamine release in the prefrontal cortex and its relatively weak affinity for some types of dopamine receptors suggest that this drug may exert its therapeutic influence in part by increasing dopaminergic function in the prefrontal cortex.