REPEATED TREATMENT WITH THE SELECTIVE KAPPA-OPIOID AGONIST U-69593 PRODUCES A MARKED DEPLETION OF DOPAMINE D-2 RECEPTORS

U-69593, the selective kappa-opioid agonist, was repeatedly administer ed in single daily injections (0.32 mg/kg) to male, Sprague-Dawley rat s. Two or ten days later, the rats were euthanized and dopamine D-1 an d D-2 receptors were measured using [H-3]SCH 23390 or [H-3]sulpiride, respectively, in caudate putamen and nucleus accumbens. Two days after the last of three injections, dopamine D-2 receptors in the caudate p utamen were decreased by approximately 40%, with no change in D-1 rece ptors. Dopamine D-2 receptor number had returned to normal by 10 days posttreatment. In contrast, in the nucleus accumbens there was a small , nonsignificant decrease in dopamine D-2 receptors 2 days after treat ment, but a large increase (65%) after 10 days. In agreement with the changes in D-2 receptors, there was a significant downward shift in th e locomotor activity curve for the D-2 agonist quinpirole after a 2-da y withdrawal. There were no differences in either the total amount of dopamine taken up or in the IC50 for cocaine to inhibit dopamine uptak e following this treatment, suggesting that the dopamine transporter a nd presynaptic terminals were intact. The results of these studies dem onstrate that repeated administration of a selective kappa-opioid agon ist induces long-term alterations in dopamine D-2 receptors. Furthermo re, the finding that these changes in receptor number require both rep eated injections and a withdrawal time greater than 1 day suggests tha t these alterations are compensatory in nature. Synapse 30:275-283, 19 98. (C) 1998 Wiley-Liss, Inc.