Neurotrophic factors are best characterized for their role in nervous system development and differentiation, although more recently they have been implicated in the regulation of neural plasticity in adult animals. The major objective of the application is to study such a role for neurotrophic factors in the neural plasticity that accompanies chronic exposure to drugs of abuse. This competing renewal focuses on interactions between two neurotrophic factors, BDNF and GDNF, and the actions of two drugs of abuse, morphine and cocaine, at the level of the mesolimbic dopamine system, a neural pathway important for the reinforcing actions of these and other drugs of abuse. Work over the first five years of this application supports three major types of interactions between neurotrophic factors and drugs of abuse, with interesting differences and similarities exerted by BDNF versus GDNF. First, we have shown that exogenous neurotrophic factors can modify the ability of drugs of abuse to produce certain characteristic biochemical adaptations in the mesolimbic dopamine system. Exogenous neurotrophic factors also modify the rewarding and locomotor-activating effects of these drugs. Second we have demonstrated that chronic exposure to morphine or cocaine causes alterations in specific neurotrophic factor signaling proteins, and in preliminary studies, show that such alterations may contribute to the behavioral effects of these drugs. Third, by use of mutant mice and other approaches, we have provided evidence that endogenous neurotrophic factor pathways are involved in controlling an animal's responsiveness to drug exposure. The goal of the proposed studies is to further characterize these interactions and to begin the process of relating specific molecular phenomena to behavioral responses to drugs of abuse, by use of viral-mediated gene transfer and genetic mutations in mice. These proposed studies will improve our understanding of the role played by neurotrophic factors in regulating an animal's responsiveness to drugs of abuse. Moreover, in a general sense, the studies will utilize models of addiction to better understand the continued influence of neurotrophic factors in controlling mesolimbic dopamine function in the fully differentiated, adult brain.
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