Discriminatory roles for D1 and D2 dopamine receptor subtypes in the in vivo control of neostriatal cyclic GMP

Abstract

The D1 and D2 subtypes of the dopamine receptor have been distinguished by their opposing effects on levels of neostriatal cyclic adenosine monophosphate (cAMP). The studies reported here show that the content of cyclic guanosine monophosphate (cGMP) in the mouse neostriatum is modulated by dopaminergic drugs in a manner which also discriminates D1 and D2 receptors. D1 receptor stimulation with SKF 38393 produced up to 90%, dose-related increases in neostriatal cGMP, whereas D1 antagonism with SCH 23390 decreased cGMP by 30% and blocked the increase induced by SKF 38393. D2 receptor stimulation with quinpirole did not alter cGMP levels whereas D2 antagonism increased cGMP by 40-60% after haloperidol and by up to 100% after sulpiride. The increases in neostriatal cGMP levels following D1 agonism were potentiated in an additive manner by haloperidol. Thus, neostriatal cGMP content is positively controlled by D1 agonism and negatively controlled by or unlinked to the D2 receptor. The reciprocal control of neostriatal cGMP levels by D1- and D2-selective compounds may contribute to the separate as well as combined actions of D1 and D2 ligands.