Common profile of D1 receptor antagonists and atypical antipsychotic drugs revealed by analysis of dopamine turnover.

1. Selective antagonists of dopamine D1 and D2 receptors enhanced 3-methoxytyramine (3-MT) accumulation in the striata and accumbens of tranylcypromine pretreated rats. Selective D1 and D2 agonists produced opposite effects. The smaller changes produced by the D1 agonists and antagonists were probably mediated by neuronal feedback, whereas the larger effects produced by the D2 ligands predominantly reflected pharmacological actions at prejunctional dopaminergic autoreceptors. 2. Atypical antipsychotics evoked small increases in 3-MT similar to the effects of the selective D1 inhibitors, whereas the mixed D1/D2 antagonists mimicked the selective D2 inhibitors by inducing much larger elevations in 3-MT. 3. gamma-Butyrolactone, an inhibitor of dopaminergic neuronal firing, dose-dependently decreased 3-MT accumulation in both the striata and accumbens. 4. gamma-Butyrolactone pretreatment abolished the small increases in 3-MT induced by the selective D1 antagonists and the atypical antipsychotics and also the large increases produced by the mixed D1/D2 antagonists. By contrast, gamma-butyrolactone only partially reversed the marked elevation of 3-MT evoked by the selective D2 antagonists. 5. The above data suggest that in vivo the atypical antipsychotics behave predominantly as selective D1 antagonists.