In the previous period, supported by DA 03025, we uncovered several sites of cocaine action: a site associated with the neuronal uptake of serotonin, a site associated with the neuronal uptake of dopamine, and a site associated with sodium channels. In the present application we wish to study another site of action, the monoamine storage vesicle, and to assess the involvement of the sites in behavioral effects of cocaine, in three types of experiments: 1. Correlation of neurochemical and behavioral effects of cocaine. We will study tolerance and sensitization to effects of cocaine on locomotor and stereotyped behavior upon chronic administration of cocaine by either intermittent, daily injections or continuous regimens by minipumps or pellets. To explain the tolerance or sensitization effects, we will test specific hypotheses that involve a modulation of neuronal dopamine and serotonin uptake systems, of storage of dopamine and serotonin into neuronal storage vesicles, or of sodium channels. The possible involvement of storage vesicles and sodium channels in the acute effects of cocaine will be assessed. 2. Correlation of neurochemical and behavioral effects after in vivo blockade of cocaine binding sites with metaphit. Our recent experiments indicate that we can use metaphit, a PCP analog with an acylating function to irreversibly block cocaine binding sites on the dopamine carrier. We plan to study the turnover of cocaine binding sites by measuring the reappearance of binding and of cocaine's behavioral effects after in vivo blockade with metaphit. 3. Model systems for studies of cocaine effects. A more detailed study of cocaine's interactions with monoamine carriers will be carried out with the help of systems less complex than the brain. We plan to use resealed plasma membrane vesicles and blood platelets for the study of monoamines transporters in plasma membranes, and bovine chromaffin granules for the study of catecholamine storage vesicles.
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