Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens

Abstract

The reinforcing properties of cocaine are thought to be primarily mediated by the release of dopamine (DA) in the nucleus accumbens (N ACC). The extracellular concentration of DA in the N ACC was monitored with in vivo microdialysis procedures during ongoing cocaine self-administration to achieve a more detailed understanding of how DA mediates the reinforcing effects of cocaine. A dose-dependent decrease in lever pressing behavior occurred as the dose of cocaine was increased. The mean number of lever presses (in 20 min intervals) for 0.25, 0.50 and 0.75 mg/infusion doses was5.6 ± 0.7, 3.3 ± 0.3and2.4 ± 0.3, respectively. However, a simple inverse relationship did not occur between lever pressing behavior and the total amount of cocaine injected. Lever pressing behavior significantly increased cocaine intake as the dose of cocaine was increased. The total amount of cocaine intake that occured during the 3 h self-administration period of the 0.25, 0.50 and 0.75 mg/infusion doses was12.0 ± 1.8mg, 14.6 ± 0.37mg and16.6 ± 1.2mg. Correspondingly, the extracellular concentration in the N ACC was increased and maintained at significantly higher levels as the dose of cocaine was increased. The average concentration of DA that occurred during the self-administration of 0.25, 0.50 and 0.75 mg/infusion doses of cocaine was269 ± 26%, 381 ± 21%and464 ± 49% of the basal DA concentration. As dose is increased, a corresponding increase occurs in both cocaine intake and in the extracellular concentration of DA in the N ACC. These results indicate that the level of reinforcement that occurs during cocaine self-administration is dependent on dose. Although within a single self-administration session, DA levels are stable, between self-administration sessions, the level does change with dose. Across doses, animals do not titrate cocaine infusions to maintain a specific level of DA in the N ACC. Apparently, just maintaining a specific extracellular level of DA in the N ACC does not maximize the reinforcing effects of cocaine.