Alterations in the dopamine system underlie a variety of psychiatric disorders that include Schizophrenia and drug addiction. In order to understand how these alterations arise, it is necessary to first understand the basic mechanisms that regulate how dopamine mediates transmission. One of the key brain regions where many drugs of abuse, including cocaine, mediate their rewarding and reinforcing properties is within the nucleus accumbens. Despite a wealth of literature examining the interaction between cocaine and the dopamine system in the accumbens and an understanding of the cellular and molecular singling pathways of dopamine receptors, relatively little is known in regards to how the synaptic release of dopamine leads to the activation of post-synaptic receptors. At the heart of the problem lies the fact that dopamine receptors in many terminal regions including the accumbens do not directly evoke post-synaptic currents. As a result it has not been possible to directly measure a dopamine mediated synaptic event using conventional electrophysiological approaches. Thus, unlike the advances that have been made in understanding the actions of other neurotransmitters, relatively little is known in regards to how dopamine receptors encode the strength and timing of synaptic dopamine release. This proposal will use a novel approach to directly measure D2 dopamine receptor activation in the nucleus accumbens. By using the endogenous dopamine receptor to detect the synaptic release of dopamine, this proposal will record from medium spiny neurons in the nucleus accumbens and dorsal striatum to (1) define the time course and duration of a physiologically relevant dopamine synaptic event (2) determine how tonic and phasic patterns of dopamine release are encoded by post-synaptic D2-receptors and (3) determine how cocaine blocks the reuptake of dopamine following release to differentially alter the activation of D2-receptors during tonic and phasic dopamine release. These experiments will test the central hypothesis that activation of D2-receptors following dopamine release occurs in a fast, tightly regulated synaptic manner. The proposed studies are expected to be significant in that they have to potential to be the first examination of a dopamine mediated synaptic event in any forebrain terminal region. Insights into the specific mechanisms that regulate dopamine transmission under physiological conditions are expected to directly lead to testable hypothesis regarding the dysregulations in this system that occur as a result of chronic drug abuse and addiction.
Determining how dopamine signals in the brain is a key first step to understanding how this system becomes altered as a result of chronic drug use. A better understanding of the events linking dopamine release to its physiological actions will be significant as it has the potential to direct new strategies for the treatment of drug abuse and addiction.
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