Abstract

The effects of continuous exposure to selective dopaminergic agonists were examined in mice with unilateral 6-hydroxydopamine-induced lesions of the corpus striatum. Continuously infusing the D1 agonists, SKF 38393, SKF 75670 and Cy 208-243 with the use of implanted Alzet minipumps initially produced rotational behavior, but this effect decreased during the first 2 days and then stopped completely during days 3 to 7 of drug infusion. Infusion of the D2 agonists quinpirole and N-0437 also produced rotational behavior but, in contrast to the results seen with the D1 agonists, the rotational response remained present throughout the 7 days of drug exposure. The desensitization produced by continuous exposure to SKF 38393 was selective for the D1 system, as animals exposed continuously to SKF 38393 failed to rotate to an acute challenge dose of SKF 38393 but had a normal rotational response to quinpirole. SKF 75670 and CY 208-243 were less selective than SKF 38393; continuous exposure to SKF 75670 and CY 208-243 decreased the response to an acute injection of D1-agonists by 98 and 95%, respectively, and to that of D2-agonists by 64 and 38%, respectively. Infusing the peripherally acting D1 agonist, fenoldopam, or the inactive isomer (-)-SKF 38393 failed to produce desensitization, suggesting that SKF 38393-induced desensitization is produced by an action at D1 receptors within the central nervous system. These results demonstrate that the D1 system can be desensitized independently from the D2 system and that there are different mechanisms for the long term regulation of D1 and D2 dopaminergic systems.