Multiple cocaine unit doses are redundant when measuring the magnitude of effect of dopamine receptor antagonists on self‐administration

The change in frequency of cocaine self‐administration as a function of unit dose is widely assumed to represent a graded pharmacodynamic response. An alternative pharmacokinetic (PK)/pharmacodynamic (PD) theory (Norman and Tsibulsky, Brain Res. 1116:143, 2006) states that the increasing intervals at higher unit doses is due to the increasing time required for the higher cocaine concentrations to decline to the same minimum concentration (satiety threshold) at which a quantal PD response occurs. Competitive antagonists should increase the cocaine satiety threshold but the effect magnitude should be independent of the agonist unit dose. Rats self‐administered cocaine at unit doses between 0.75 and 6 μmol/kg, the D1 dopamine receptor antagonist SCH23390 (15 nmol/kg i.v.) was administered and the session continued. Despite the apparent SCH23390‐induced rightward shift with the graded response model the maximal response and EC50 were not measurable. However, the magnitude and time‐course of the SCH23390‐induced increase in satiety threshold was independent of the cocaine unit dose, consistent with the PK/PD model assuming a quantal response. It is concluded that the rate of cocaine self‐administration as a function of unit dose represents a dose‐duration of response not a dose‐magnitude of response curve and when assessing the effects of antagonists the use of more than one unit dose of cocaine is redundant.