The interaction between the dopaminergic and glutamatergic systems governs normal behavior and is perturbed in many psychiatric disorders including schizophrenia. Hypofunction of the D1 family of receptors, to which the D 1 and D 5 subtypes belong, is a typical feature of schizophrenia. Here we have used confocal live cell imaging of neurons to examine the distinct roles of the D 1 and D 5 receptors in the intra-neuronal interaction with the glutamatergic system. Using fluorescently tagged D 1 or D 5 expressed in cultured striatal neurons, we show that both receptor subtypes are primarily transported via lateral diffusion in the dendritic tree. D 1 is to a much larger extent than D 5 expressed in spines. D 1 is primarily expressed in the head whereas D 5 is largely localized to the neck of the spine. Activation of N-methyl-d-aspartic acid (NMDA) receptors slowed the diffusion rate and increased the number of D 1 positive spines, while no effect on D 5 diffusion or spine localization could be observed. The observed differences between D 1 and D 5 can be attributed to structural differences in the C-terminus and its capacity to interact with NMDA receptors and PSD-95. Identification of a unique role of D 1 for the intra-neuronal interaction between the dopaminergic and glutamatergic systems will have implications for the development of more specific treatments in many neuropsychiatric disorders.