Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration

Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t(½)) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters in rats. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self-administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self-administer cocaine, SCH23390 had no effect on the plasma steady-state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t(½) at a dose that accelerated cocaine self-administration. A constant cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self-administration. SCH23390, or the D₂ dopamine receptor antagonist (-)eticlopride, reinstated self-administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist-induced acceleration of cocaine self-administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first-order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased interinjection intervals.