Jpet210690 311..315

The change in frequency of cocaine self-administration as a function of the unit dose is widely assumed to represent a graded pharmacodynamic response. Alternatively, a pharmacological theory states that during maintained selfadministration, a quantal response occurs at a minimum maintained cocaine concentration (satiety threshold). Rats selfadministered cocaine at unit doses spanning an 8-fold range from 0.75 to 6 mmol/kg. Despite an approximately 7-fold difference in the interinjection intervals, there were no differences in the plasma cocaine concentration at the time of lever press across this range of unit doses, consistent with the satiety threshold representing an equiactive cocaine concentration. Because self-administration always occurs when cocaine concentrations decline back to the satiety threshold, this behavior represents a process of automatic back titration of equiactive agonist concentrations. Therefore, the lower frequency of self-administration at higher unit doses is caused by an increase in the duration of the cocaine-induced satiety response, and the graded dose-frequency relationship is due to cocaine pharmacokinetics. After the interinjection intervals at a particular unit dose were stable, rats were injected with the competitive D1–like dopamine receptor antagonist R-(1)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine (SCH23390; 15 nmol/kg intravenously) and the session continued. At all cocaine unit doses, SCH23390 accelerated self-administration with a concomitant increase in the calculated satiety threshold, and these equiactive cocaine concentration ratios were independent of the cocaine unit dose. Therefore, the measurement of antagonist potency requires only a single unit dose of cocaine, selected on the basis of convenience, and using multiple cocaine unit doses is redundant.