Olfactory receptor neurons (ORNs) have been assigned the incredible task of distinguishing between over 10,000 odor molecules. Not only must ORNs decipher the quality of odors, they must also provide the brain with intensity information. Recent studies have made considerable progress in identifying and characterizing the components of signal transduction machinery in ORNs. Odors binding to receptor proteins on olfactory cilia initiate a G-protein-mediated second messenger cascade that results in the transient elevation of cAMP or IP3. Both second messengers gate specific ion channels in the ciliary membrane, resulting in the generation of receptor potentials. Olfactory mucus provides the perireceptor environment in which the initial steps of the transduction of a chemical odor signal to an electrical receptor potential occur. Extrinsic autonomic and trigeminal innervation controls mucus secretion and may release neurotransmitters into the mucus. The presence of antioxidant chemicals in the mucus suggests that the mucus environment is permissive for neurotransmitter persistence yet the actions of those neurotransmitters are unclear. The sensitivity of ORNs to cAMP-generating odors is determined by both the sensitivity of the receptor proteins and the sensitivity of the cyclic nucleotide gated (CNG) channel. One possible role for neurotransmitters released into olfactory mucus is to modulate ORNs odor sensitivity. Potential sites for modulation include the receptor proteins, transduction cascades, and effector channels. The work in this proposal will test the hypotheses that the neurotransmitter dopamine is present in olfactory mucus, acts on D2 dopamine receptors on ORN dendrites and modulates the sensitivity of the system by changing basal levels of cAMP production. Our model suggest that the presence of dopamine in the mucus is under autonomic control and that increases or decreases in dopamine would increase or decrease the sensitivity of ORNs. This model fits with observations that stimulation of the trigeminal system decreases odor sensitivity in frogs, and that the psychophysical perception of odor intensity decreases after exposure to noxious substances (trigeminal stimuli). These studies may be clinically relevant to diseases where dopaminergic pathways are disturbed (Parkinson's) and which display decreased olfactory sensitivity as an early symptom. The work in this proposal will determine the modulatory role of dopamine on ORNs and will provide insights into how peripheral dopaminergic pathways may be involved in disease-related reduced olfactory sensitivity.