Life Sciences, Vol. 36, pp. 1941-1948 Pergamon Press Printed in the U.S.A. SCH23390 CAUSES PERSISTENT ANTIDOPAMINERGIC EFFECTS IN VIVO: EVIDENCE FOR LONGTERM OCCUPATION OF RECEPTORS David W. Schu]z, Laura Staples and Richard B. Mailman Departments of Psychiatry and Pharmacology Biological Sciences Research Center University of North Carohna School of Medicine Chapel H~ll, NC 27514 (Received in final form March 7, 1985) Suaunary SCH23390 has neurochemlcal properties characteristic of a specific D~ dopamlne receptor antagonist. However, it is a potent inhibitor of dopamine-medlated behaviors which previously had been thought to be linked to D2 receptors. The metabohsm 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 dechned below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamlne 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 dopamlne--stlmulated adenvIate 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. Dopamlne receptors have generally been divided into two categories, with the D~ class linked to the stimulation of cyclic AMP (cAMP) synthesis by dopamlne, and the D2 class either unrelated to adenvlate cyclase activation or linked to its inhibition (1). SCH23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-lH--3-benzazepine-7-ol] has been shown to have the biochemical and neurochemical properties expected of a specific D1 receptor antagonist, exhibiting nanomolar potencies at ~nhlblting dopam~ne-stlmulated adeny]ate cyclase activity (2,3,4) and competing for [3H]-piflutlxol binding (2,5), whereas its K~ f o r displacing IUH]-splperone is several orders of magnitude higher (2,3,5). More recently, characterizations of the binding of [3H]-SCH23390 have revealed that a number of dopaminergic ligands successfully compete for specific blndlng of this radiohgand (6,7). Among these is cis-flupenthlxol, a frequently--used DI antagonist, which is at least fifteen tlmes as potent as haloperidol, chlorpromazine, or thioridazlne at displacing [3H]-SCH23390 from membranes of rat corpus striatum (6,7). Moreover, regional specific binding of [3H]-SCH23390 Is hlghly correlated wlth the presence of dopamlne termlnals (7). These binding data, coupled with reports of potent inhlbltion of dopamlne- stlmulated adenylate cyclase as discussed above, strongly suggest that SCH23390 acts specifically at the DI class of dopamine receptors. Prevlous reports have demonstrated that a high correlatlon exlsts between the affinity of an antagonist for D2 dopamine receptors (as determined by [3H]- splperone displacement) and its abihty to cause important acute physlologlcal 0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.