Repeated exposure to cocaine administration results in a progressive and enduring enhancement in the motor stimulant effect induced by subsequent drug challenge. This phenomenon, is termed behavioral sensitization and forms part of the basic pathological mechanisms involved in drug addiction. The present proposal is aimed at studying the NE modulatory effects on the cellular mechanisms of cocaine actions in the VTA during the development of cocaine sensitization. Initial experiments will investigate if NE transmission mediates cocaine enhancement of dopaminergic VTA cell activity in response to prefrontal cortex stimulation. Experiments will include systemic and iontophoretic administration of NE antagonists. Comparisons between cocaine sensitized and saline control rats will be made. The hypothesis to test is that cocaine sensitization will produce an increase in NE modulation of glutamate-excitation in the VTA induced by prefrontal cortex. stimulation. Additional studies will investigate if NE mediates the enhanced glutamate-induced VTA excitation observed with cocaine sensitization. Iontophoretic glutamate liberation together with NE agonists and antagonists' administration will be employed to assess whether the development of sensitization involves an enhancement of NE modulation of glutamate tone in the VTA. A third experiment will determine if NE modulation of VTA synaptic properties is enhanced by the development of cocaine sensitization. Whole cell patch recording techniques in in vitro slices will be employed. The hypothesis to test is that cocaine sensitization will provide and increase in spike frequency adaptation, after hyperpolarization and after hyperpolarization currents in the VTA, which will render this area more excitable and prone to develop behavioral sensitization. Finally, the last objective is to determine the contribution of NE transmission in the expression of cocaine sensitization. The completion of these experiments will provide important information on whether a dysfunction of NE modulatory properties is an important factor in the development and expression of cocaine sensitization. A clear understanding of NE changes in the above condition will increase our knowledge of the specific role of the noradrenergic system in cocaine addictive processes. and might provide possible avenues for therapeutic pharmacological interventions.
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