Abstract
The time course of the dopamine receptor antagonist‐induced acceleration of cocaine self‐administration may correspond to the time to achieve maximum fractional occupancy. If so, the time to maximal response (Tmax) will be proportional to antagonist affinity. Male Sprague‐Dawley rats self‐administered cocaine (unit dose of 3 μmol/kg) at regular intervals. The cocaine concentration at the time of each self‐administration (agonist Cmin) was calculated. A series of 9 antagonists spanning a 10,000‐fold range of affinities for D2‐like dopamine receptors was administered i.v. and the effect of each antagonist on the calculated cocaine Cmin was determined.All of the antagonists accelerated cocaine self‐administration with a concomitant increase in the calculated cocaine Cmin. The antagonist doses that produced approximately equivalent increases in the maximum cocaine Cmin ranged from 0.015 to 4 μmol/kg. The mean Tmax values across this series of antagonists ranged from approximately 5 min to 120 min. Furthermore, the antagonist Tmax values were inversely related to their KD values across this set of antagonists.These data are consistent with the hypothesis that the agonist Tmax reflects the time course of the increase in antagonist fractional occupancy of D2‐like dopamine receptors. It is concluded that the Tmax is related to antagonist affinity.Supported by DA018538 and ASPET SURF program.
Published Version
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