Dopamine D3 receptor antagonism—still a therapeutic option for the treatment of schizophrenia

The potential of D3 receptor antagonism to treat positive, negative, and cognitive symptoms of schizophrenia is reviewed on the basis of preclinical results and preliminary clinical data. Dopamine D3 receptors are expressed in mesencephalic, limbic, and cortical areas relevant to psychotic and cognitive symptoms of schizophrenia. As expected, selective dopamine D3 receptor antagonists are not effective in antipsychotic animal models, reflecting D2 receptor antagonism. However, selective D3 receptor antagonists affect electrical activity of dopamine neurons in the ventral tegmental area similar to atypical antipsychotics, counteract effects produced by NMDA glutamate receptor blockade, and enhance cortical dopamine and acetylcholine in microdialysis. In contrast to dopamine D2 receptor antagonists, D3 antagonists positively influence a variety of social and cognitive behaviors in rodents, including tests representing cognitive flexibility and executive function, which are both impaired in schizophrenia patients. Despite considerable affinity for D3 receptors, the second-generation antipsychotics clozapine, risperidone, and olanzapine when administered to patients with schizophrenia seem not to occupy D3 receptors sufficiently to derive any conclusion on a D3-mediated therapeutic benefit. ABT-925, the first selective D3 receptor antagonist, was recently studied in patients with schizophrenia. It produced cognitive signals but did not achieve sufficient D3 receptor occupancy to test the hypothesis that D3 receptor antagonism is of therapeutic value to treat symptoms of schizophrenia. Based on mechanistic and experimental considerations and due to the fact that D3 receptor antagonism can inhibit extrapyramidal symptoms and produce neither anhedonia nor metabolic adverse effects, the development and clinical testing of newer D3 receptor antagonists with high potency at D3 receptors, enabling sufficient receptor occupancy, is highly warranted.