SCH23390 causes persistent antidopaminergic effects in vivo: evidence for longterm occupation of receptors.

SCH23390 has neurochemical properties characteristic of a specific D1 dopamine receptor antagonist. However, it is a potent inhibitor of dopamine-mediated behaviors which previously had been thought to be linked to D2 receptors. The metabolism of SCH23390 following parenteral administration to rats was much more rapid in the periphery than in brain, and SCH23390 had behavioral effects long after its circulating concentration had declined below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamine was attenuated in striatal homogenates taken from rats treated with SCH23390 as much as twelve hours before sacrifice. Pretreatment with cis-flupenthixol, a compound with equivalent D1 potency in vitro, failed to inhibit dopamine-stimulated adenylate cyclase activity one or four hours following injection, despite the fact that this dose produced significant behavioral effects. These data indicate that SCH23390 may act with unusual tenacity at certain sites in the central nervous system.