Although the Van Rossum hypothesis of dopamine receptor overactivity in schizophrenia is supported by the antagonism of, or reduced dopamine neurotransmission at, dopamine D2 receptors by antipsychotics, it has been claimed that the antipsychotic (-)-OSU6162 has a very low affinity for the dopamine D2 receptor, and has only autoreceptor dopamine D2 receptor-stimulating action, and, therefore, in order to explain its clinical action, the drug must stimulate dopamine D2 receptors that are defective or underactive in schizophrenia. Because the mode of action of (-)-OSU6162 is critical in determining whether psychosis is associated with dopamine D2 receptor overactivity or deficit activity, we measured the potency of (-)-OSU6162 on the binding of [3H]domperidone and on the incorporation of [35S]-GTP-gamma-S into human cloned dopamine D2 receptor-containing cells. We found that (-)-OSU6162 had a dissociation constant of 35 nM at the functional high-affinity site of the dopamine D2 receptor, stimulated the incorporation of [35S]-GTP-gamma-S above 100 nM, and inhibited the incorporating action of 1 microM dopamine with an inhibitory dissociation constant, Ki, of 27 nM, all being properties of a dopamine partial agonist. While not excluding the possibility that dopamine underactivity may exist in the mesocortical system in psychosis, the antipsychotic action of (-)-OSU6162 is consistent with dopamine overactivity in psychosis.