Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists

Abstract

The release and metabolism of dopamine in the mouse caudate-putamen were determined after the oral administration of antipsychotic drugs at doses equal to or sixfold greater than the ED₅₀ dose for their inhibition of apomorphine-induced climbing. Dopamine release was equated with concentrations of 3-methoxytyramine (3-MT) and metabolism was equated with concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Like the D-1 antagonists SCH 23390 and SKF 83566, most antipsychotic agents with an atypical preclinical profile suggestive of low extrapyramidal symptomatology (CGS 10746B, flumezapine, CL 77328, rimcazole, clozapine, RMI 81582, and fluperlapine) never increased dopamine release and produced variable increases in dopamine metabolism. Other atypical antipsychotics (thioridazine, mesoridazine, melperone) increased dopamine release at only one dose tested but increased dopamine metabolism at most doses. Antipsychotic agents associated with extrapyramidal side effects (setoperone, perlapine, haloperidol, chlorpromazine, and metoclopramide) increased dopamine release and metabolism at almost every dose tested. Thus, atypical antipsychotics increase the metabolism but not release of dopamine at behaviorally effective doses. The resemblance of these minimal effects on dopamine release to those obtained with D-1 antagonists that also have an atypical preclinical profile suggests that a mechanism related to D-1 receptor antagonism may contribute to the action of atypical antipsychotics.