NEUROPEPTIDES AND SALT APPETITE
Principal Investigator: FRANCIS FLYNN
Abstract: 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.
Funding Period: 1997-05-01 - 2009-08-31
more information: NIH RePORT
- delta2 opioid receptor agonist facilitates mean arterial pressure recovery after hemorrhage in conscious ratsShawna M McBride
Department of Zoology, University of Wyoming, Laramie, Wyoming, USA
Shock 23:264-8. 2005..The results show that after hemorrhage, during the recompensatory period, stimulation of delta(2) opioid receptors leads to improved MAP, and this recovery may involve a change in baroreflex sensitivity...
- Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetaminesShawna M McBride
Graduate Neuroscience Program, Dept of Zoology and Physiology, Univ of Wyoming, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 295:R899-905. 2008..These results indicate that early life experience with low- and high-sodium diets, during the prenatal or early postnatal period, is a stress that produces long-term changes in responsiveness to amphetamines and to subsequent stressors...
- Trafficking of tachykinin neurokinin 3 receptor to nuclei of neurons in the paraventricular nucleus of the hypothalamus following osmotic challengeD Jensen
Graduate Neuroscience Program, University of Wyoming, Department 3166, Laramie, WY 82071, USA
Neuroscience 155:308-16. 2008..NK3R antibody specificity was confirmed by small interfering (SI) RNA technology. This study establishes that the NK3R is trafficked to the nucleus of PVN neurons following a peripheral osmotic challenge...
- Tachykinin neurokinin 3 receptor signaling in cholecystokinin-elicited release of oxytocin and vasopressinGwendolen E Haley
Neuroscience Program, University of Wyoming, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 294:R1760-7. 2008..Therefore, central NK3R signaling is required for OT and VP release in response to CCK administration...
- Centrally administered vasopressin cross-sensitizes rats to amphetamine and drinking hypertonic NaClShawna M McBride
Graduate Neuroscience Program, Department of Zoology and Physiology, University of Wyoming, 1000 E University Ave, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 293:R1452-8. 2007..This pattern of cross-sensitization links central VP signaling, amphetamine, and sodium deficiency, and therefore it may play a role in the cross-sensitization between sodium appetite and amphetamines...
- Tachykinin NK3 receptor contribution to systemic release of vasopressin and oxytocin in response to osmotic and hypotensive challengeGwendolen E Haley
Graduate Neuroscience Program, University of Wyoming, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 293:R931-7. 2007..HDZ-induced VP and OT release was eliminated by pretreatment with 500 pmol SB-222200. Therefore, NK3R activation contributes significantly to the systemic release of both VP and OT in response to osmotic and hypotensive challenges...
- Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamusThu T Dinh
Programs in Neuroscience, Washington State University, Pullman, WA 99164 6520, USA
Am J Physiol Regul Integr Comp Physiol 291:R870-9. 2006..Lack of an AVP response to insulin-induced hypoglycemia in intact rats therefore indicates that responses to hypovolemia and hypoglycemia are mediated by different catecholamine neurons under distinct sensory controls...
- Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetaminesShawna M McBride
Graduate Neuroscience Program, Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 291:R1192-9. 2006..These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine...
- Cardiovascular alteration and treatment of hypertension: do men and women differ?Shawna M McBride
Department of Zoology and Physiology and Graduate Neuroscience Program, University of Wyoming, Laramie, 82071, USA
Endocrine 28:199-207. 2005..Therefore, this review will focus on sex-related differences in the heart and vasculature, and treatments for cardiovascular disease, such as hypertension...
- Agonist and hypertonic saline-induced trafficking of the NK3-receptors on vasopressin neurons within the paraventricular nucleus of the hypothalamusGwendolen E Haley
Dept of Zoology and Physiology, Univ of Wyoming, Laramie, WY 82071, USA
Am J Physiol Regul Integr Comp Physiol 290:R1242-50. 2006..These results show that hyperosmolarity stimulates the local release of an endogenous ligand in the PVN to bind to and activate NK3R on vasopressinergic neurons...
- Intraventricular injections of tachykinin NK3 receptor agonists suppress the intake of "salty" tastes by sodium deficient ratsFrancis W Flynn
Department of Zoology and Physiology, Graduate Neuroscience Program, University of Wyoming, Laramie, WY 82071, USA
Behav Brain Res 166:1-8. 2006....
- Intraventricular injections of tachykinin NK3 receptor agonist reduce the gain of the baroreflex in unrestrained ratsFrancis W Flynn
Department of Zoology and Physiology and Graduate Neuroscience Program, University of Wyoming, Box 3166 University Station, Laramie, WY 82071, USA
Exp Neurol 193:118-24. 2005..These results show that NK3 receptor stimulation modulates the baroreflex that is independent of any action of vasopressin...
- Blockade of NK3R signaling in the PVN decreases vasopressin and oxytocin release and c-Fos expression in the magnocellular neurons in response to hypotensionGwendolen E Haley
Graduate Neuroscience Program, University of Wyoming, Laramie, Wyoming 82071, USA
Am J Physiol Regul Integr Comp Physiol 295:R1158-67. 2008..Therefore, NK3R signaling in magnocellular neurons has a critical role for the release of VP and OT in response to hypotension...