Prefrontal DA transmission at D₁ receptors and the pathology of schizophrenia

The current view on the dopamine (DA) hypothesis of schizophrenia postulates a cortical/subcortical imbalance: subcortical mesolimbic DA projections might be hyperactive, resulting in hyperstimulation of D ₂ receptors and positive symptoms, whereas mesocortical DA projections to the prefrontal cortex might be hypoactive, resulting in hypostimulation of D₁ receptors, negative symptoms, and cognitive impairment. Although the subcortical abnormalities are relatively well established now, the evidence for cortical hypodopaminergia is just emerging. This article will review current evidence for prefrontal hypodopaminergia in schizophrenia, with special emphasis on positron emission tomography (PET) studies measuring cortical D₁ receptors in schizophrenia. The presentation of the clinical data will be introduced by a brief overview of the function of prefrontal DA systems, both at the cellular and cognitive level. The impact of antipsychotic drugs on prefrontal DA function will also be reviewed. We will conclude with the formulation of several models of altered prefrontal DA transmission at D₁ receptors in schizophrenia.