The nucleus accumbens (NAc) is a basal forebrain structure located at the crossroads of limbic and motor circuits. The NAc is thought to play an important role in a variety of cognitive processes and has been suggested as a possible site of schizophrenic pathophysiology and antipsychotic drug (APD) action. However, little is known regarding the physiological properties of individual NAc neurons and the regulatory factos which influence their activity. This series of studies will use combinations of extracellular single cell recording, microiontophoresis, electircal stimulation, and anatomical tracing techniques to: (1) identify the neurophysiological properties of individual NAc neurons with respect to their waveforms, firing rates and patterns, topographical distribution, efferent and afferent connections, conduction velocities and absolute refractory periods, (ii) characterize the roles of D-1 and D-2 DA receptors in mediating the neuroregulatory influences of DA within the NAc, (iii) determine the possible interactions between D-1 and D-2 receptors within the NAc and their possible role in neuromodulation, and (iv) explore the possible sites and mechanisms of action of antipsychotic drugs within the NAc and in NAc-A10 feedback processes which have been implicated in mediating APD effects on A10 DA neurons. The rationale for these projects is that identification of the specific neuronal systems involved in the actions of APDs should eventually lead to the development of new treatment strategies which might interact specifically with relevant neuronal systems and avoid systems responsible for the extrapyramidal side effects (EPSE) which complicate pharmocotherapy with standard APDs. The underlying hypothesis directing these studies is that the NAc is an essential site of APD action and that this nucleus reacts to chronic APD treatment in a manner different from that of the nigrostriatal DA system. Thus, the elucidation of the physiology and pharmacology of the NAc, particularly the roles of DA receptors, should greatly advance our understanding of the mechanisms of action of APDS. Hopefully, such understanding will aid in the development of new and better medications for the treatment of schizophrenia. The long-term objective of this project is to identify the particular roles of limbic and motor pathways in initiating, maintaining and altering various aspects of behavior.
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