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.

Olfactory behavior is important for food seeking and animal survival. On the other hand, olfactory dysfunction is a common feature of several diseases such as psychiatric disorders, neurodegeneration, and COVID-19 (1–3). Interestingly, the olfactory ability can be regulated by feeding status and external environments (4, 5). Recent studies have made progress in identifying the neural circuits and circulating hormones in olfactory regulation (6–11). However, the peripheral targets modulating olfactory ability remain relatively unexplored (12).Dopamine (DA) is a monoamine neurotransmitter (13, 14), which plays important roles in a variety of brain functions. DA is released by dopaminergic neurons in the central nervous system. In addition, DA can be released by sympathetic nerves in the peripheral tissues including the olfactory mucosa (OM) (15–18). The sympathetic innervation of rodent OM originates predominantly from the superior cervical ganglion (SCG) (17). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for DA synthesis (19). Intriguingly, the Th mRNA is locally translated in the sympathetic nerve axons, which facilitates local DA synthesis (20, 21).There are two types of DA receptors based on sequence homology and function: The excitatory D1-like receptors (DRD1 and DRD5) and inhibitory D2-like receptors (DRD2–DRD4) (22). Activation of DRD2, a Gα_i/o-coupled receptor, can reduce the intracellular levels of cyclic adenosine monophosphate (cAMP). Drd2 is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs (23–28). In the central nervous system including the olfactory bulb (OB), DA-DRD2 signaling plays important roles in regulating synaptic transmission and plasticity (29–33). However, the function and regulation of DA-DRD2 signaling in the peripheral tissues are relatively less understood.Here we show that DRD2 is expressed in the cilia and somata of mature olfactory sensory neurons (OSNs) in mice. We provide evidence that DA-DRD2 signaling has a tonic inhibition on OSN activity and olfactory function in mice. Intriguingly, hunger greatly reduces the N4-acetylcytidine (ac⁴C) modification of Th mRNA and local DA synthesis in mouse OM, which causes the olfactory enhancement during starvation. We further show that inhibition of local DA synthesis or DRD2 receptor in mouse OM recapitulates enhanced olfactory abilities during starvation. Collectively, these results reveal nasal DA and DRD2 receptor as the potential peripheral targets for olfactory regulation.