Drug addiction is an immense medical and social problem worldwide. A central focus of current research is elucidating the long-term molecular and cellular alterations in the mesolimbic system that subserve addiction. Neurochemical, electrophysiological and behavioral studies have highlighted an important role for alterations in the glutamatergic system in this process. However the molecular mechanisms mediating these changes are unclear. Recent studies have identified Narp as an immediate early gene involved in clustering AMPA receptor subunits at synaptic sites. Narp, therefore, could be contributing to alterations in excitatory transmission induced by neuronal stimulation. In preliminary studies we found that Narp expression is induced in the ventral tegmantal area (VTA) with chronic cocaine administration and may therefore play an important role in mediating alterations in glutamatergic transmission induced by drugs of abuse. As an initial step in investigating its role, we plan to: (A) Determine key aspects of Narp regulation by drugs of abuse. In particular, we shall define the time course and regional distribution of Narp expression following cocaine administration, and assess whether Narp expression is also altered by other drugs of abuse. (B) Develop methods to manipulate expression of Narp in the VTA using the herpes simplex virus vector system.
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