Distinct Roles of Dopamine Receptor Subtypes in the Nucleus Accumbens during Itch Signal Processing

Ventral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing two dopamine receptors subtypes within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing. SIGNIFICANCE STATEMENT Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of dopamine D1 receptor (D1R) and D2R in the nucleus accumbens (NAc) shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc lateral shell (LaSh) play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.