Administration of neurotensin (NT) into the dopamine (DA)-containing nuclei of the mesolimbic system; nucleus accumbens (NACB) and ventral tegmental area (VTA); in the brain inhibits gastric acid secretion and affords gastric mucosal protection against cold water restraint (CWR) induced gastric mucosal injury. The unifying hypothesis is that CWR- induced hypothermia reduces NT activity in the mesolimbic system by reducing NT message, causing a reduction of dopamine activity and a reduction in alpha and beta adrenergic activity in these nuclei resulting in either increased vagal tone or decreased sympathetic tone which will then result in increased rates of gastric acid secretion or reduced endogenous mucosal prostaglandin synthesis. The proposed studies will better define l) the effect of CWR on mesolimbic levels of NT, DA, and NT mRNA and the B-max and K-D for NT and DA receptors; 2) the role played by central adrenergic and dopaminergic receptor activation; and 3) the mechanism(s) by which NT enhances gastric mucosal prostaglandin activity. Concentrations of mesolimbic NT, DA, and NT mRNA, and NT and DA receptor number (B-max) and affinity (K-D) will be measured at various time intervals (15-120 min) during CWR and following the stereotaxic administration of a NT, DA or specific receptor antagonists into the NACB or VTA. These studies will provide information regarding the role of NT in the mesolimbic nuclei during CWR and control of NT and DA receptor activity during CWR. Central (mesolimbic) or systemic pretreatment with alpha1, alpha2, beta1, beta2, DA1, or DA2 receptor agonists, antagonists, and truncal vagotomy before 1) central NT administration followed by CWR; or 2) pentagastrin administration will provide information regarding the role of central adrenergic and dopaminergic mediation of antisecretory and protective effects of central NT. The effect of specific pharmacological dopaminergic, adrenergic, and truncal vagotomy preceding central NT administration, on gastric mucosal prostaglandin generation will provide information regarding the potential mechanism(s) by which central NT enhances gastric mucosal prostaglandin generation. These studies will enhance our understanding of central control of gastric mucosal function and may provide new avenues through which mucosal defense mechanisms can be enhanced.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK038198-04A3
Application #
2140315
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1987-01-01
Project End
1999-08-31
Budget Start
1995-09-15
Budget End
1996-08-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Surgery
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Zhang, L; Xing, L P; Demers, L et al. (1989) Central neurotensin inhibits gastric acid secretion: an adrenergic mechanism in rats. Gastroenterology 97:1130-4

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