The interaction of lisuride (Lysenyl, Spofa), an ergot derivative, with serotonergic and dopaminergic receptors and with adenylate cyclase was studied in homogenates of rabbit brain. In frontal cortex, lisuride interacts with serotonin receptors as shown by its ability to compete with [3H]serotonin, [3H]spiroperidol and [3H]lysergic acid diethylamide for their receptor binding sites, with respective IC50 values of 14, 1.0 and 3.7 nM. The IC50 for displacement of [3H]spiroperidol by lisuride in frontal cortex was increased by the GTP analog, 5'-guanylylimidodiphosphate, indicating an agonist-like interaction. Lisuride is extraordinarily potent in stimulating serotonin-sensitive adenylate cyclase in this brain region, with maximal stimulations occurring at 0.1 nM lisuride. In caudate nucleus, lisuride interacted with both serotonergic and dopaminergic receptor sites as labeled by [3H]serotonin, [3H]lysergic acid diethylamide and [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, with IC50 values ranging from 2.0 to 7 nM. Lisuride did not stimulate adenylate cyclase in caudate nucleus. In summary, lisuride is a very potent stimulator of serotonin-sensitive adenylate cyclase in rabbit frontal cortex and can interact with serotonin and dopamine receptor binding sites in rabbit cortex and caudate nucleus.