Evidence for a distinct D1-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain.

Dopamine and the D1 receptor agonist SKF 38393 activate the phospholipase C-mediated hydrolysis of phosphoinositides in brain slices. This action is selectively inhibited by SCH-23390, thus suggesting its mediation through the dopamine D1 receptor. To determine if the dopamine receptor that mediates phosphoinositide hydrolysis is the adenylyl cyclase-linked D1 receptor or a different subtype of the dopamine D1 receptor, 20 benzazepine compounds that were previously characterized as selective dopamine D1 receptor agonists were tested for stimulation of phosphoinositide hydrolysis in rat striatal slices and for activation of adenylyl cyclase in rat striatal membranes. The compounds displayed a range of potencies and efficacies in stimulating adenylyl cyclase or phosphoinositide hydrolysis. Compounds such as SKF 81427 and SKF 38393 were as efficacious as dopamine in stimulating phosphoinositide hydrolysis, whereas other compounds, including SKF 85174 and SKF 86284, although showing high efficacy in stimulating cyclic AMP, failed to stimulate inositol phosphate formation. There was no correlation between the potencies (r = 0.016; p > 0.95) or efficacies (r = -0.294; p > 0.24) of the tested compounds in stimulating cyclic AMP formation and phosphoinositide hydrolysis. These observations indicate that the D1-like dopamine receptor that mediates phosphoinositide hydrolysis is pharmacologically distinct from the classic D1 receptor that is coupled to stimulation of cyclic AMP formation.