In the previous period, supported by DA 03025, we studied the properties (regional and subcellular distribution, structure-activity relationships, behavioral sensitization and tolerance effects, irreversible block by acylation, inositol response) of several sites of cocaine action associated with the uptake of serotonin and dopamine, voltage-dependent sodium channels, and the carrier of synaptic vesicles. In the present application we wish to extend the study to other sites of action, and compare effects of cocaine hydrochloride and cocaine freebase (crack) as follows: 1. Correlation of neurochemical and behavioral effects of cocaine. We will study tolerance (after continuous infusion by minipumps) and sensitization (after intermittent injections) to effects of cocaine on locomotor and stereotyped behavior of rats. To explain the behavioral effects, we will test specific hypotheses that involve a modulation of the release of dopamine and serotonin in dopaminergic terminal fields and cell body areas and an interaction between serotonin and dopamine. In addition, we wish to study the possibility that a regulation at the level of sodium channels in the limbic system underlies the development of seizure activity upon repeated cocaine treatment and the protection offered by long-term carbamazepine. 2. Model systems. Cocaine's interactions with dopamine storage processes will be studied in bovine striatal synaptic vesicles and bovine chromaffin granules; we will focus on events subsequent to uptake of dopamine by the transporter. To further characterize cocaine's action on the transporter involved in neuronal uptake of dopamine, plasma membrane vesicles will be prepared from purified synaptosomes from bovine striatum; we plan to assess the relationship between the substrate recognition site for dopamine uptake and the binding site for cocaine. 3. Crack. We plan to administer cocaine as crack, the freebase form, to mice in a smoking machine. We will assess the pharmacokinetics and metabolism of crack, the effect of crack administration on ex vivo monoamine uptake, and the changes in locomotor and stereotyped behavior upon acute and chronic crack exposure.
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