The primary goal of this project is to investigate the cellular and molecular mechanisms through which adrenal steroids mediate their behavioral actions on the control of sodium appetite. Adrenal steroids act upon the brain to arouse sodium appetite and do so by activating the brain angiotensin system as well as by suppressing inhibitory neuropeptide systems such as oxytocin (OT) and the tachykinins (TKs). These effects are mediated by genomic mechanisms involving mineralocorticoid and glucocorticoid receptors that are expressed throughout the brain acting in concert with non-genomic mechanisms. We have uncovered a novel, nongenomic action of adrenal steroids in the amygdala that has focussed our attention on this brain region, as well as upon the GABA-benzodiazepine receptor system. The interrelated Specific Aims are intended to elaborate on the genomic and non-genomic mechanisms of adrenal steroid action in terms of the neuropeptide systems and the GABA-benzodiazepine system and their interactions with each other in the arousal of sodium appetite.
The Specific Aims i nvestigate: 1) Genomic control of salt appetite involving mineralocorticoid and glucocorticoid receptors using the antisense technique; 2) Non-genomic control of salt appetite in the amygdala of the rat brain using local application of steroids and benzodiazepine agonists and antagonists; 3) Involvement of genomic control of the expression of key neuropeptides that are either excitatory or inhibitory for salt appetite; 4) Interaction of genomic and non-genomic mechanisms at the level of neuropeptides and GABAa receptors. Specific hypotheses to be tested include the notion that a genomic mechanism involving mineralocorticoid receptors maintains key components of the GABAa and neuropeptide systems in a state where the non-genomic actions can take place. Another hypothesis is that the non-genomic steroid action involves steroid metabolism to products that act directly upon the GABAa receptor to increase its efficacy. This research is relevant to understanding the role of behavioral and neural control of dietary salt intake, which contributes to the establishment and maintenance of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
2P01MH043787-06A1
Application #
2579108
Study Section
Project Start
Project End
Budget Start
1995-10-01
Budget End
1996-09-30
Support Year
6
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lucas, Louis R; Grillo, Claudia A; McEwen, Bruce S (2007) Salt appetite in sodium-depleted or sodium-replete conditions: possible role of opioid receptors. Neuroendocrinology 85:139-47
Sakai, Randall R (2004) The future of research on thirst and salt appetite. Appetite 42:15-9
Daniels, Derek; Fluharty, Steven J (2004) Salt appetite: a neurohormonal viewpoint. Physiol Behav 81:319-37
Lundy Jr, Robert F; Caloiero, Vince; Bradley, Courtney et al. (2004) Furosemide-induced food avoidance: evidence for a conditioned response. Physiol Behav 81:397-408
Lucas, Louis R; Grillo, Claudia A; McEwen, Bruce S (2003) Involvement of mesolimbic structures in short-term sodium depletion: in situ hybridization and ligand-binding analyses. Neuroendocrinology 77:406-15
Fitts, Douglas A; Thornton, Simon N; Ruhf, Alexandra A et al. (2003) Effects of central oxytocin receptor blockade on water and saline intake, mean arterial pressure, and c-Fos expression in rats. Am J Physiol Regul Integr Comp Physiol 285:R1331-9
Hines, John; Fluharty, Steven J; Yee, Daniel K (2003) Structural determinants for the activation mechanism of the angiotensin II type 1 receptor differ for phosphoinositide hydrolysis and mitogen-activated protein kinase pathways. Biochem Pharmacol 66:251-62
Tamura, R; Norgren, R (2003) Intracranial renin alters gustatory neural responses in the nucleus of the solitary tract of rats. Am J Physiol Regul Integr Comp Physiol 284:R1108-18
Lucas, Louis R; Reagan, Lawrence P; Akama, Keith T et al. (2003) Decreases in neurokinin-3 tachykinin receptor-immunoreactive and -mRNA levels are associated with salt appetite in the deoxycorticosterone-treated rat. Brain Res 960:252-8
Bello, Nicholas T; Lucas, Louis R; Hajnal, Andras (2002) Repeated sucrose access influences dopamine D2 receptor density in the striatum. Neuroreport 13:1575-8

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