Cortical D2 dopamine receptor (Drd2) have mostly been examined in the context of cognitive function regulation and neurotransmission modulation of medial prefrontal cortex by principal neurons and parvalbumin positive, fast-spiking, interneurons in schizophrenia. Early studies suggested the presence of D2 receptors in several cortical areas, albeit with major technical limitations. We used combinations of transgenic reporter systems, recombinase activated viral vectors, quantitative translatome analysis, and high sensitivity in situ hybridization to identify D2 receptor expressing cells and establish a map of their respective projections. Our results identified previously uncharacterized clusters of D2 expressing neurons in limbic and sensory regions of the adult mouse brain cortex. Characterization of these clusters by translatome analysis and cell type specific labeling revealed highly heterogeneous expression of D2 receptors in principal neurons and various populations of interneurons across cortical areas. Transcript enrichment analysis also demonstrated variable levels of D2 receptor expression and several orphan G-protein-coupled receptors coexpression in different neuronal clusters, thus suggesting strategies for genetic and therapeutic targeting of D2 expressing neurons in specific cortical areas. These results pave the way for a thorough re-examination of cortical D2 receptor functions, which could provide information about neuronal circuits involved in psychotic and mood disorders.

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The release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety. Further, the D1R high-efficacy agonist SKF 81297 and low efficacy agonist (±)-SKF-38393 inhibit α-amino-3-hydroxy-5-methyl-4isoxazolepropionic receptor (AMPAR) currents in the ACC. Paradoxically, the D1R antagonists SCH-23390 and SCH 33961 when co-applied with D1R agonists produced a robust short-term synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands. Overall, our data indicate that absence of D1Rs in the ACC enhanced peripheral sensitivity to mechanical stimuli and D1R activation decreased glutamatergic synaptic transmission in ACC neurons.