EFFECTS OF CHRONIC SCH 23390 OR ACUTE EEDQ ON THE DISCRIMINATIVE STIMULUS EFFECTS OF SKF 38393

Three groups of rats (n = 8/group) were trained in a two-lever, food-reinforced drug discrimination paradigm to discriminate the D1 agonist SKF 38393 (SKF; 8.0 mg/kg, IP) from saline. After acquisition of the discrimination, the dose-response function for SKF (2.0-16 mg/kg, IP) was determined using a cumulative dosing procedure. In one group, the SKF dose-response function was redetermined 1 week after a regimen of 0.25 mg/kg of the D1 antagonist SCH 23390 (SCH), IP, once/day for 10 days, again 1 week after a second regimen of 0.5 mg/kg SCH, IP, twice/day for 10 days, and a third time after a regimen of 1.0 mg/kg SCH, IP, twice/day for 21 days. SKF dose-response functions were redetermined in a group of control rats after identical injection regimens of saline. In the third group of rats, SKF dose-response functions were redetermined 24 h after an injection of N-ethoxycarboxyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (irreversible antagonist) vehicle; again 24 h after an injection of 3.0 mg/kg; again 48 h after 6.0 mg/kg EEDQ; and finally 48 h after two consecutive daily injections of 6.0 mg/kg EEDQ (12 mg/kg total). The dose-response function for the percentage of responses that occurred on the SKF lever (%DL) shifted significantly to the left following the second regimen of SCH; there was no further shift after the third regimen. The effects of SKF on response rate were unchanged by SCH administration. Repeated administration of saline did not alter the SKF dose-response function for %DL or response rate. Administration of EEDQ vehicle or EEDQ also failed to alter the SKF dose-response functions for %DL. However, EEDQ itself decreased response rate and enhanced the rate-decreasing effects of SKF. Binding studies conducted 14 days after SCH exposure indicated a significant increase in B(max) for D1 binding sites in the corpus striatum in SCH-treated rats. B(max) tended to increase in the nucleus accumbens, but did not achieve statistical significance. EEDQ treatment decreased B(max) in corpus striatum 48 h after administration, but had no effect in nucleus accumbens. K(d) was unchanged in either region by either treatment. The results demonstrate that repeated administration of the D1 antagonist SCH can sensitize rats to the DS effects of the D1 agonist SKF, perhaps via an up-regulation of D1 receptors in the brain. Further, the results suggest that drug discrimination is a useful in vivo bioassay for measuring changes in CNS receptors.