Measures of drug-seeking behavior in animals provide models that can be used to screen potential treatments for drug craving and relapse in humans and to study the neural mechanisms involved. These measures include operant responding for drug when it is no longer available (i.e., extinction) and reinstatement of responding either by administration of drug or presentation of drug-associated cues. The objective of the proposed research is to examine the role of monoamine (MA) systems in cocaine-seeking behavior using the extinction/reinstatement model. Animals trained to lever press for food will be trained to self-administer cocaine or will receive yoked administration of saline. After responding has been established, they will be given 14 daily 3-hr training sessions, followed by a final 12-hr """"""""binge"""""""" session. Later, drug-seeking behavior, as well as MA overflow in the nucleus accumbens and amygdala, will be assessed in 3 test phases: phase 1 will assess operant responding during extinction; phase 2 will assess reinstatement of responding by presentation of cocaine-associated cues; phase 3 will assess reinstatement of responding following a cocaine injection. The following day, food-seeking behavior will be examined to determine whether changes observed previously are specific to drug-seeking. The first experiment will examine the relationship between changes in drug-seeking behavior and MA overflow during cocaine withdrawal in separate groups of animals tested 6 hr, 30 hr, 7 or 28 days after the last self-administration session. Next, the effect of chronic treatment with desmethylimipramine (DMI), a MA reuptake inhibitor with some anti-craving efficacy, on drug-seeking behavior and MA overflow will be investigated. MA receptor density will also be assayed post-mortem. It is hypothesized that cocaine withdrawal will produce a time-dependent increase in drug-seeking behavior that will correlate with neurochemical changes in MA systems, and that DMI treatment during withdrawal will attenuate drug-seeking behavior and reverse the neurochemical changes. Characterizing time-dependent changes in drug-seeking behavior and MA systems will provide a better understanding of cocaine withdrawal and relapse, and may provide insight into the neural mechanisms of drug-seeking behavior. This information is crucial for developing pharmacologic treatments for cocaine craving and relapse. The last experiments will investigate the hypothesis that the dopamine D3-- preferring agonist 7-OH-DPAT attenuates drug-seeking behavior. If confirmed, the findings would suggest a new pharmacologic treatment strategy for cocaine dependence.
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