An enduring alteration in the behavioral response to an acute psychostimulant challenge is produced by repeated psychostimulant pretreatment. Termed behavioral sensitization, this example of neuronal plasticity can culminate in paranoid psychosis, panic attacks and anxiety disorders. Using a rat animal model, sensitization can be studied in two temporally and spatially distinct components, initiation and expression. The study of initiation attempts to describe the neural and cellular substrates upon which repeated drug administration impinges to establish the long-term behavioral alterations. The study of expression endeavors to identify enduring changes in neural and cellular function that mediate the augmented behavioral response. During the previous funding period it was shown that initiation of sensitization to cocaine arises from drug action in the ventral tegmental area (VTA) and that the expression of sensitization is partly the result of altered excitatory amino acid (EAA) and dopamine transmission in the nucleus accumbens. In this proposal, this research orientation will be amplified by using microdialysis to measure not only extracellular dopamine, but also amino acids and enkephalin. Further, biochemical measures of Ca+2-dependent signal transduction will be obtained to discern the intracellular consequences of alterations in transmitter release. The overall career objective is to characterize the neural basis of sensitization to psychostimulants. During the previous funding period this was accomplished primarily by behavioral and microdialysis measures, and an expansion into the study of changes in signal transduction is proposed. This will involve training in other laboratories and constitutes a major advantage of the RCDA, without which, extensive teaching commitments would inhibit my growth into the study of signal transduction. Thus, the RCDA permits the PI to apply a multidimensional research approach to the problem of sensitization by employing many techniques to discern the neural mechanisms of behavioral sensitization. A multidimensional approach provides cross correlations between different technical avenues of study, and is considered necessary to accurately describe the neural mechanisms regulating a complex behavior such as sensitization to cocaine.
