The mesoprefrontal cortical (MC) dopamine (DA) system may play a key role in the development of schizophrenia. This application proposes to characterize this system using the newly developed in vitro technique. The long-term goal of this project is to understand how the MC DA system functions in the brain and how it may be altered by antipsychotic drug (APD) treatment. Information obtained from these studies may provide new insights into the pathogenesis of schizophrenia and the mechanism of action of APDs. Compared with other DA neurons, MC DA neurons are more active and particularly sensitive to stress. They also show distinct responses to APDs. To determine whether some of these unique properties are mediated intrinsically, identified MC DA cells will be recorded in a brain slice preparation. To determine whether they possess unique membrane properties that make them more active and more sensitive to synaptic inputs, their membrane properties will be compared with those other DA neurons. To determine whether a lack of DA autoreceptors plays a role in the observed differences between MC and other DA neurons, their function will be studied in nigral DA neurons. It will be investigated whether DA autoreceptors in nigral DA neurons inhibit excitatory input-induced responses, and whether MC DA neurons, due to a lack of autoreceptors, are more responsive to excitatory inputs. It will be determined whether APDs by blocking DA autoreceptors, selectively enhance the excitability of other DA neurons but not MC DA neurons. In the prefrontal cortex (PCC), DA has been suggested to be hypoactive in schizophrenia. However, since how DA acts in the PFC is still controversial, it is difficult to predict what the consequences of this hypoactivity would be and how it may be related to the hypofrontality observed in schizophrenia. To better understand the function of DA in the PFC, the second part of this application proposes to study the effect of DA on identified PFC neurons and correlate the response of a cell to DA with the cell's physiological, morphological and anatomical properties. To obtain information on how PFC DA influences mesolimbic and nigrostriatal systems, the effects of DA on PFC neurons projecting to the accumbens and the caudate will be compared. To test whether DA excites GABA interneurons, as suggested previously, they will be identified and recorded. Using selective DA agonists and antagonists, the receptors responsible for different DA effects will be determined. The application also proposes to compare the effects of clozapine and haloperidol on DA-induced responses of different PFC neurons. Such comparison may help us understand why clozapine is more effective in treating negative symptoms and lacks extrapyramidal side effects.
