Schizophrenia is a prevalent disease of profound morbidity. Its treatment was revolutionized by the advent of the neuroleptics. These drugs reduce psychotic symptoms by blocking the synaptic action of dopamine. Consequently, pathologic dopaminergic synaptic transmission, in particular, that of mesocorticolimbic dopamine neurons has become the focus of attempts to elucidate the neurophysiology of the schizophrenic psychosis. Mechanistic understanding of the functioning of these synapses, however, has remained inferential, contributing to the controversy over how neuroleptics act at these critical sites. What has been needed to gain a deeper understanding of the function of mesocorticolimbic dopamine neurons has been a method of examining their synapses individually. In preliminary studies, one subclass of mesocorticolimbic dopamine neurons, those projecting to the nucleus accumbens, has been successfully labelled in midbrain cell cultures, using retrograde transport of fluorescent latex microspheres. In vitro, these cells show their characteristic electrophysiology, known from studies in intact preparations and brain slice work. Examining the synapses formed by such identified cells now makes approachable four seminal questions: (1) What are the functional properties of mesocorticolimbic dopamine synapses? (2) How do neuroleptics act at these synapses, both acutely and chronically? (3) How does dopamine interact with its autoreceptors, found on the terminals of certain mesocorticolimbic dopamine neurons? (4) And, what role do the co-transmitters cholecystokinin and neurotensin play? Characterization of mesocorticolimbic dopamine synapses would provide a significant step toward discerning the role of the mesocorticolimbic dopamine system in the schizophrenic psychosis. Moreover, understanding neuroleptic action on dopamine synapses might lead to the development of improved pharmacologic treatments. In the longer term, insight might be gained into treatment of neuroleptic-refractory symptoms, those of the deficit state of chronic schizophrenia, which bring about the tremendous morbidity of the illness.
