Olfactory regulation by dopamine and DRD2 receptor in the nose

Olfactory behavior is important for animal survival, and olfactory dysfunction is a common feature of several diseases. Despite the identification of neural circuits and circulating hormones in olfactory regulation, the peripheral targets for olfactory modulation remain relatively unexplored. In analyzing the single-cell RNA sequencing data from mouse and human olfactory mucosa (OM), we found that the mature olfactory sensory neurons (OSNs) express high levels of dopamine D2 receptor (Drd2) rather than other dopamine receptor subtypes. The DRD2 receptor is expressed in the cilia and somata of mature OSNs, while nasal dopamine is mainly released from the sympathetic nerve terminals, which innervate the mouse OM. Intriguingly, genetic ablation of Drd2 in mature OSNs or intranasal application with DRD2 antagonist significantly increased the OSN response to odorants and enhanced the olfactory sensitivity in mice. Mechanistic studies indicated that dopamine, acting through DRD2 receptor, could inhibit odor-induced cAMP signaling of olfactory receptors. Interestingly, the local dopamine synthesis in mouse OM is down-regulated during starvation, which leads to hunger-induced olfactory enhancement. Moreover, pharmacological inhibition of local dopamine synthesis in mouse OM is sufficient to enhance olfactory abilities. Altogether, these results reveal nasal dopamine and DRD2 receptor as the potential peripheral targets for olfactory modulation.