There is now clinical evidence that l-sulpiride has antidepressant effects when administered at low, non-neuroleptic doses. Down-regulation of beta-receptor-linked adenylate cyclase is a well-documented adaptive response to chronic administration of antidepressant drugs. In this study, we investigated dopamine receptor and beta-adrenoceptor changes induced by chronic administration of low doses of l-sulpiride. The data indicate that striatal D1 and D2 receptor function was desensitized by the treatment, which suggests that at low doses l-sulpiride preferentially blocks D2 autoreceptors, leading to increased dopamine release. l-Sulpiride also induced a selective down-regulation of beta-receptor-associated adenylate cyclase activity in the frontal cortex, but not in the striatum, which does not receive norepinephrine projections. Taken together these data suggest that cortical noradrenergic terminals may be endowed with dopamine D2 receptors controlling norepinephrine release and that blockade of this dopaminergic inhibitory modulation may be involved in the antidepressant effects of l-sulpiride.