The nucleus accumbens (NAc) is a basal forebrain structure which is the major recipient of dopamine (DA) projections from the A10 neurons of the ventral tegmental area. The NAc serves as a relay station for signals emanating from limbic structures and destined for basal ganglia targets involved in the control of voluntary movement and has, therefore, been proposed to act as an interface between emotion and action. The role of DA within this circuit is viewed as a modulator, integrating and gating emotional and motivational variables into behavioral expression. Disturbances of DA transmission have been implicated in the pathophysiology of schizophrenic disorders and the NAc is thought to be an integral site of antipsychotic drug (APD) action. Since DA receptors are a primary sight of APD action, the specific goal of this project is to understand the functional roles of the D1 and D2 DA receptor subtypes within the NAc. The investigators' previous studies have discovered one of the most important features underlying the operations of D1 and D2 receptors, i.e., the fact that D1 receptor activation is required for (enables) the functional effect of D2 receptor agonists.
The specific aims of the project are: (1) to characterize further the roles of D1 and D2 DA receptors in mediating the neuroregulatory influences of DA within the NAc; (2) to determine the effects of DA denervation on the functional responses and interactions of D1 and D2 receptors within the NAc; (3) to determine and compare the effects of repeated stimulation of D1 and/or D2 receptors; (4) to determine and compare the effects of repeated blockade of D1 and/or D2 receptors; and (5) to investigate the mechanisms underlying the effects of D1 and D2 receptor agonists on NAc neurons. These experiments will utilize extracellular single-cell recording and microiontophoretic techniques to determine the relationship between D1 and D2 DA receptors in rats pretreated in manners designed to alter the sensitivities of the two receptors. In addition, parallel behavioral studies will determine the extent to which changes at the cellular level are manifested in behavior. The long-term objective of this research project is to understand the specific neuronal systems involved in the actions of APDs.
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