Dysfunctions of mesolimbic pathways have been postulated to underlie major neuropsychiatric disorders and drug abuse. While the role of NAC inputs in the regulation of DAergic transmission has received considerable attention, the role of DA receptor activity in modulating NAC efferent projection neurons has not been well studied. The determination of the DAergic regulation of NAC efferents and its role in cognition will provide critical insights into the behavioral consequences of abnormal mesolimbic functioning. The proposed research is designed to test the hypothesis that NAC DA inhibits the main NAC efferents - a GABAergic projection to ventral pallidal areas [specifically, to the substantia innominate (SI)]. As a result of this DA-mediated inhibition of GABA release in SI, DAergic transmission within NAC regulates the activity of basal forebrain AChergic system. This AChergic system innervates all cortical areas and thus, potently gates cortical information processing. The proposed research uses the technique of in vivo microdialysis to characterize the dynamic, trans-synaptic regulation of cortical ACh release. The pharmacological and behavioral determinants of DA (NAC), GABA (SI) and ACh (cortex) efflux will be determined in awake rats. The first series of experiments will test the hypothesis that increases in NAC DA receptor activity with local perfusions of amphetamine will decrease GABA efflux in SI and, as a result, increase ACh efflux in cortex. The second series of experiments will demonstrate that the ability of intra-NAC amphetamine to increase cortical ACh efflux can be potentiated and attenuated by drugs that increase and decrease, respectively, GABAergic transmission in SI. The final series of experiments will utilize microdialysis in task-performing animals in order to test the hypothesis that NAC DA-basal forebrain GABAergic modulation of cortical ACh selectively mediates attentional functions. These experiments will substantiate the role of mesolimbic-cortical circuits in fundamental aspects of cognitive processes, and thus will contribute to our understanding of the cognitive consequences of aberrations within these circuits.
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