The proposed work is part of the MGH, East Charlestown Program Project to the NIDA. Preliminary research has shown that cocaine induced changes in regional cerebral blood volume (rCBV), as measured by functional magnetic resonance imaging (fMRI), are more sustained in rats with a history of cocaine self-administration than in drug naive animals (i.e. rats that have performed for an equal amount of time on a food-reinforced behavior). The purpose of the investigation proposed here is to test the hypothesis that this sustained response in chronic animals correlates with an increase in the magnitude and duration of dopamine release in limbic structures of chronic animals. A second goal is to examine the hypotheses that different patterns of change in rCBV will be associated with the administration of dopamine D1 (SKF 81297, SKF 38393) and D2 (7-OH DPAT) receptor agonists to chronic as compared to naive animals. Finally, the hypothesis will be assessed that administration of non-selective serotonin (5-HT) receptor antagonists (methiothepin) and of selective 5-HT/1b/d partial agonists (GR 127935) alone and in combination with cocaine will produce distinct alterations in rCBV in chronic and naive rats. The animals will be prepared and trained at the laboratory of Behavioral Pharmacology, BU School of Medicine and then transported to the fMRI Laboratory at the Charlestown-MGH Laboratories. Use of fMRI measures of rCBV provides better time resolution of drug induced changes than do other imaging techniques. The results of this study will help to establish how chronic cocaine self- administration alters regulation by dopaminergic and serotonergic mechanisms of regional brain function over time.
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