Dopamine release and metabolism after chronic delivery of selective or nonselective dopamine autoreceptor agonists

CA Altar, B Berner, P Beall, SF Carlsen and WC Boyar

Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901.

The metabolism and release of dopamine by rat mesostriatal and mesolimbic dopamine neurons were determined after 2 or 14 days of subcutaneous administration via Alzet minipumps of a selective (CGS 15855A) or nonselective (apomorphine) dopamine autoreceptor agonist. Bioassays and high performance liquid chromatography assays showed that each drug was accurately delivered for the 2- and 14-day periods. CGS 15855A levels in the plasma and brain increased with increases in the daily dose given, although plasma levels of CGS 15855A at 14 days were less than those at 2 days for each dose. Striatal dopamine metabolism and release, assessed with dihydroxyphenylacetic acid and 3- methoxytyramine concentrations, respectively, were suppressed by 2-day treatments of 50-200 micrograms/day CGS 15855A or 250 micrograms/day apomorphine. These suppressions were potentiated by acute challenge with 1 mg/kg intraperitoneally of CGS 15855A or 2 mg/kg subcutaneously of apomorphine. In contrast, dopamine metabolism and release were unchanged after 14 days of administration of 40-400 micrograms/day of CGS 15855A or 250 micrograms/day of apomorphine, even when plasma levels of drug were as high as at 2 days. Dopamine release was decreased in only one of six groups 30 min after an additional acute injection of the agonist given for 14 days, whereas dopamine metabolism was decreased in five of six groups. Striatal dopamine levels were increased 20-57% after 14 but not 2 days of cgs 15855A followed by acute challenge with the vehicle or CGS 15855A injections. Thus, the responsiveness of dopamine neurons to the release-suppressing properties of dopamine autoreceptor agonists is mostly attenuated between 2 and 14 days of treatment. The ability of chronic CGS 15855A treatments to increase dopamine levels and, with acute CGS 15855A, to decrease DOPAC levels, indicates that autoreceptor control of dopamine metabolism is partly retained after chronic autoreceptor agonism.

Volume 33, Issue 6, pp. 690-695, 06/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics