This is the second revision of this application in which the Investigator requests five years of support. Recent data suggest that tachykinins (TKs) contribute to control of NaCl intake, in that intraventricular TK injection suppress both need-free and sodium-deficiency-induced NaCl intake. The TK receptor subtype involved appears to be the NK3 receptor, as the NK3 selective agonist is more effective in this regard than the NK1 agonist. The proposed work is an investigation of the mechanisms and brain regions involved in the effects of TKs on salt intake, concentrating on the hypothesis that the TKs alter the palatability of NaCl taste. Preliminary data are presented indicating that intraventricular administration of the NK3 receptor agonist, senktide (SENK), increases the intake of dilute NaCl concentrations and decreases the intake of more concentrated solutions (including the normally preferred concentration) in salt-replete rats. The same treatment blocks the increased acceptance of highly concentrated NaCl solutions that normally occurs in sodium-deficient rats. The hypothesis forwarded to interpret this finding is that SENK alters salt taste palatability, perhaps by increasing the intensity of the taste. To test the hypothesis that palatability is altered, the researchers will conduct the following experiments. In Experiment #1 the researchers will evaluate taste reactivity to NaCl and non sodium-containing salt solutions (LiCl, KCl) in sodium-replete and sodium-deficient rats given SENK into the lateral ventricle. The taste reactivity test entails the use of videocapture of behavioral acceptance and rejection responses elicited by delivery of solutions into the oral cavity through an implanted catheter. The participation of endogenous TKs in modulating palatability will then be evaluated in Experiment #2 by assessing reactivity to salt solutions in rats given intraventricular injections of selective TK antagonists. In Experiment #3, the same type of taste reactivity and intake experiments will be conducted, but TK agonists will be injected into gustatory and limbic nuclei to assess the possibility that these are sites where Tks act to alter NaCl taste and intake. In Experiment #4 the researchers will test the behavioral significance of the change in salt palatability induced by TKs by examining the effect of SENK on instrumental responses conditioned for NaCl reward and resistence of the instrumental response to extinction. A follow-up experiment will examine the reliance of SENK-induced effects on postingestive effects of NaCl using rats with gastric fistulas. Finally, in Experiment #5 the researchers will use multidimensional scaling to determine if sodium deficiency induced by different techniques and TKs alter taste groupings in rats tested by brief exposure to multiple tastants.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG2-BPO (01))
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University of Wyoming
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McBride, Shawna M; Culver, Bruce; Flynn, Francis W (2008) Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetamines. Am J Physiol Regul Integr Comp Physiol 295:R899-905
Jensen, D; Zhang, Z; Flynn, F W (2008) Trafficking of tachykinin neurokinin 3 receptor to nuclei of neurons in the paraventricular nucleus of the hypothalamus following osmotic challenge. Neuroscience 155:308-16
Haley, Gwendolen E; Flynn, Francis W (2008) Blockade of NK3R signaling in the PVN decreases vasopressin and oxytocin release and c-Fos expression in the magnocellular neurons in response to hypotension. Am J Physiol Regul Integr Comp Physiol 295:R1158-67
Haley, Gwendolen E; Flynn, Francis W (2008) Tachykinin neurokinin 3 receptor signaling in cholecystokinin-elicited release of oxytocin and vasopressin. Am J Physiol Regul Integr Comp Physiol 294:R1760-7
Haley, Gwendolen E; Flynn, Francis W (2007) Tachykinin NK3 receptor contribution to systemic release of vasopressin and oxytocin in response to osmotic and hypotensive challenge. Am J Physiol Regul Integr Comp Physiol 293:R931-7
McBride, Shawna M; Flynn, Francis W (2007) Centrally administered vasopressin cross-sensitizes rats to amphetamine and drinking hypertonic NaCl. Am J Physiol Regul Integr Comp Physiol 293:R1452-8
Haley, Gwendolen E; Flynn, Francis W (2006) Agonist and hypertonic saline-induced trafficking of the NK3-receptors on vasopressin neurons within the paraventricular nucleus of the hypothalamus. Am J Physiol Regul Integr Comp Physiol 290:R1242-50
Dinh, Thu T; Flynn, Francis W; Ritter, Sue (2006) Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamus. Am J Physiol Regul Integr Comp Physiol 291:R870-9
McBride, Shawna M; Culver, Bruce; Flynn, Francis W (2006) Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines. Am J Physiol Regul Integr Comp Physiol 291:R1192-9
Flynn, Francis W (2006) Intraventricular injections of tachykinin NK3 receptor agonists suppress the intake of ""salty"" tastes by sodium deficient rats. Behav Brain Res 166:1-8

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