Heart disease is a significant preventable health threat because one of the factors in the etiology of heart disease is hypertension, which is linked to salt consumption. Appropriately, there has been considerable interest in identifying the neurochemical systems controlling salt intake. Stimulation of the tachykinin NK3 receptor using selective agonists is known to exert a inhibitory effect on salt intake. We found that stimulation of NK3 receptors inhibit salt intake by decreasing the oral sensory property of salt and potentiating salt ingestion-contingent negative feedback. Also, in support of an interaction with the sensory properties of salt, we found that stimulation of brain NK3 receptors activates (based on c-Fos expression) neurons in gustatory and vagal afferent pathways. The goals of the present proposal are to determine the sensory and neuroanatomical mechanisms by which NK3 receptor agonists inhibit salt intake and to identify the endogenous tachykinin ligand for the NK3 receptor.
Aim 1 will test the hypothesis that stimulation of NK3 receptors causes a suppression of salt intake that is not dependent on the hormonal status of the animal. Exogenous administration of NK3 receptor agonists suppress salt intake but the endogenous tachykinin ligand that stimulates the NK3 receptor to suppress salt intake is unknown.
Aim 2 will test the hypothesis that Neurokinin B (NKB) is the endogenous tachykinin that inhibits salt intake. We discovered that immunoneutralization of NKB facilitated hypertonic salt intake. This finding provides strong support for our working hypothesis that NK3 receptor agonists are mimicking the inhibitory action of endogenous NKB on salt intake.
Aim 3 will test the hypothesis that NKB-expressing and NK3 receptor expressing neurons are activated during the normal inhibition (satiation) of salt appetite. The comparison of the pattern of Fos expression in rats that are sodium deficient (no access to NaCl) to that of rats allowed to drink NaCl to satiation will reveal functional tachykinergic systems that are active during the inhibition of salt intake. The research problem is an important one and the role of tachykinins in sodium regulation is deserving of a great deal of attention. The proposed research will provide new information on the identity of the endogenous tachykinin that has been indirectly studied through the use of synthetic NK3 receptor agonists and the sensory mechanisms by which stimulation of NK3 receptors inhibit salt intake. Successful completion of the proposed work will expand the knowledge base on brain mechanisms controlling bodily fluid homeostasis.
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