Guidance molecules interact to orchestrate dopamine plasticity in adulthood

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The dopamine systems of the brain are involved in cognition, motor activity, motivation and reward. These systems and their connections are remarkably plastic, undergoing changes throughout life. Repeated exposure to stimulant drugs, such as amphetamine, results in changes in dopamine systems resulting in long-lasting increases in sensitivity to the effects that these drugs, and to other life events that activate the dopamine systems. The general aim of my research project is to identify mechanisms that bring about changes in sensitivity in dopamine function and behavior in adulthood, rendering individuals more (or less) vulnerable to subsequent exposure to drugs or to stressors. To this end I will study how amphetamine induces such changes in the adult brain. Identification of these processes will have important implications for our understanding of how ‘experience’ can alter dopamine circuitry and, in turn, dopamine-mediated behaviors. The enduring nature of changes in the dopamine system in the adult brain suggests reorganization of the circuitry by re-activation of factors that are normally involved in organizing neuronal wiring during development. Netrin-1 is a protein that plays a fundamental role in the organization of neuronal connectivity during development and we have recently shown that (1) netrin-1 receptors are highly expressed by dopamine neurons in the adult brain, (2) repeated amphetamine exposure in the adult upregulates the expression of netrin-1 receptors, (3) netrin-1 receptor upregulation by amphetamine is required for the development of amphetamine induced dopamine plasticity. This research proposal is now aimed at identifying how precisely netrin-1 and netrin-1 receptors mediate amphetamine-induced dopamine plasticity in the adult.