The dopaminergic system plays an important role in the etiology of schizophrenia, and most antipsychotic drugs exert their functions by blocking dopamine D2 receptors (D2Rs). Since the signaling strength mediated by D2Rs is regulated by internalization and degradation processes, it is crucial to identify molecules that modulate D2R localization at the cell surface. Here, we show that the neural cell adhesion molecule (NCAM) promotes D2R internalization/desensitization and subsequent degradation via direct interaction with a short peptide in the third intracellular loop of the D2R. NCAM deficiency in mice leads to increased numbers of D2Rs at the cell surface and augmented D 2R-signaling as a result of impairedD2Rinternalization. Furthermore, NCAM-deficient mice show higher sensitivity to the psychostimulant apomorphine and exaggerated activity of dopamine-related locomotor behavior. These results demonstrate that, in addition to its classical function in cell adhesion, NCAM is involved in regulating the trafficking of the neurotransmitter receptor D2R as well as receptor-mediated signaling and behavior, thus implicating NCAM as modulator of the dopaminergic system and a potential pharmacological target for dopamine-related neurological and psychiatric disorders. Copyright © 2009 Society for Neuroscience.