Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats.

According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.