Involvement of brain dopamine systems on neurotensin-induced protection against stress gastric lesions

doi:10.1016/0006-8993(86)90705-5

Brain Research

Volume 381, Issue 1, 27 August 1986, Pages 159-163

https://doi.org/10.1016/0006-8993(86)90705-5 Get rights and content

Abstract

We have previously demonstrated that intracisternal (i.c.) administration of neurotensin (NT), a brain and gastrointestinal tridecapeptide, potently inhibits gastric ulcer formation induced by cold-restraint stress (CRS) in rats. This study evaluated the effect of i.c. NT (17.9 nmol) or vehicle (10 μl of 0.9% NaCl) on the development of CRS-induced gastric ulcers and on dopamine (DA) concentrations and DA turnover (DOPAC/DA) in selected brain regions after 0, 1, 2 and 3 h of CRS. As anticipated, and in confirmation of previous findings, NT significantly reduced the incidence and severity of CRS gastric ulcers in a time-dependent manner. Neurotensin significantly decreased DA concentration and DA turnover in the striatum. In the nucleus accumbens, however, NT produced a decrease in DA concentration and a concomitant increase in DA turnover after 2 and 3 h of CRS. No significant effects of brain NT on DA concentration and DA turnover were observed in the hypothalamus or olfactory tubercles. These findings suggest that the anti-ulcer effect of brain NT may be mediated, at least in part, by a differential activation of the mesolimbic and nigrostriatal DA systems.

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Cited by (27)

Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats
2010, European Journal of Pharmacology
Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE₂ content and proton pump activity. The dopamine D₁ receptor agonist (A 68930) and antagonist (SCH 23390), and D₂ receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150 min) and chronic unpredictable stress (two different types of stressors for 7 days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60 mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25 mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1–0.5 mg/kg) and quinpirole (0.1–0.5 mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10–50 μg/ml) inhibited the gastric H⁺ K⁺-ATPase activity comparable to positive control omeprazole, while sulpiride (10–50 μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D₁ agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions.
Neurochemical changes in mice following physical or psychological stress exposures
2002, Behavioural Brain Research
An investigation on the mechanism of neurochemical changes in physically or psychologically stressed mice was carried out. Physical stress was induced by electric foot shocks (2 mA for 5 s at 30-s intervals), and psychological stress was induced by emotional stimuli from electric foot-shocked mice using a communication box. The serum and brain calcium levels and immunohistochemical brain dopamine levels increased, and the ethanol-induced sleeping time was prolonged following exposure to these stimuli. The effects of electric foot shocks on these physiological parameters were greater than those of emotional stimuli. In the psychologically stressed mice, serum and brain calcium levels significantly increased 15 and 60 min, respectively, after the start of exposure to stimuli. Also, the immunohistochemical dopamine levels in the neostriatum and nucleus accumbens regions after 60 min of exposure to psychological stress were higher by 23% (P<0.01) and 27% (P<0.01), respectively, than those in unstressed control mice. Moreover, the ethanol-induced sleeping time was prolonged by approximately 60–100% (P<0.01) in mice exposed to psychological stress for 30–120 min. The effect of emotional stimuli to prolong the ethanol-induced sleeping time was inhibited by intracerebroventricular administration of W-7 (a calmodulin antagonist) or α-methyltyrosine (an inhibitor of tyrosine hydroxylase). In light of previous reports that calcium activates dopamine synthesis in the brain via a calmodulin-dependent system, it is suggested that physical or psychological stimuli induce an increase in the brain calcium level, and this increased calcium level in turn enhances dopamine synthesis in the brain. Subsequently, an increased dopamine level induces various physiological changes related to stress-dependent phenomena.
Gastric ulcer formation in cold-stressed mice related to a central calcium-dependent-dopamine synthesizing system
1998, Neuroscience Letters
Stress ulceration of the stomach in mice was investigated from the aspect of the calcium/calmodulin-dependent dopamine synthesizing system in the brain. Cold stress was induced in mice by restraining them at 4°C. Serum and brain calcium levels were increased by cold stress, and an increased brain calcium level was found to enhance dopamine synthesis and a successively increased brain dopamine level induced gastric ulcer formation. Development of gastric ulcers elicited by cold stress was significantly decreased by i.p. pretreatment with EDTA (1 μmol/mouse, 1 h before restraint) or α-methyltyrosine (a tyrosine hydroxylase inhibitor, 100 mg/kg, 24 h before restraint), and was further significantly increased by pretreatment with CaCl₂ (40 μmol/kg, 1 h before restraint). These findings suggest that the development of gastric ulcers in cold-stressed mice may be linked with the enhancement of calcium/calmodulin-dependent catecholamine synthesis in the brain.
Stress, the brain, and the gastric mucosa
1997, American Journal of Surgery
Exposure of rats to 2 hours of cold water restraint is associated with both macroscopic and microscopic gastric mucosal injury. Administration of neurotensin into the lateral ventricle or into the nucleus accumbens, one of the mesolimbic dopamine system nuclei, is associated with protection when given before exposure to cold water restraint. Under conditions of cold water restraint, pretreatment with central neurotensin is associated with maintenance of gastric mucosal blood flow and an increase in endogenous gastric mucosal PGE₂ activity. In addition, pretreatment with 6-hydroxy dopamine into the mesolimbic nuclei, which depletes them of endogenous dopamine, prior to exposure to cold water restraint, ameliorates the protective effect of central neurotensin. Centrally administered neurotensin inhibits basal, pentagastrin-, carbachol-, and 2-deoxy-D-glucose-induced but not histamine-induced gastric acid secretion. This antisecretory effect is ameliorated by parenteral pretreatment with haloperidol and domperidone. Taken together, these observations support the hypothesis that centrally administered neurotensin, particularly into the nuclei of the mesolimbic dopamine system, confers protection against gastric mucosal injury produced by 2 hours of cold water restraint. This affect may be due, in part, to inhibition of acid secretion and maintenance of mucosal blood flow mediated by an increase in gastric mucosal PGE₂ activity.
The role of 5-HT<inf>3</inf> receptors in the anti-ulcer effect of calcitonin
1994, General Pharmacology
- 1.
  1. The aim of the present study was to determine the role of 5-HT₃ receptors of the gastroprotective effect of salmon calcitonin (sCT) and sCT-induced changes in gastric, hepatic, brain and brainstem glutathione (GSH) and lipid-peroxidation (LP) levels in rats subjected to cold-immobilization stress.
- 2.
  2. Stress exposure resulted in ulcer formation and a decrease in GSH levels of the liver, brain and brainstem and an increase in gastric and hepatic LP (P <0.05).
- 3.
  3. sCT prevented stress-induced gastric ulcer development (P < 0.01) and reversed the decrease in hepatic and brain GSH levels (P < 0.05).
- 4.
  4. In the present study, a 5-HT₃ receptor antagonist, ICS 205 930 was used. Interestingly, the effect of the blocker on GSH and LP levels of the tissues studied was similar to those of sCT.
- 5.
  5. ICS 205 930 dose dependently reversed the anti-ulcer effect of sCT although it did not antagonize the effect of sCT on GSH and LP levels, but it seemed to show an additive interaction for brain and brainstem GSH and gastric LP levels with sCT.
The role of the neurotransmitters acetylcholine and noradrenaline in the pathogenesis of stress ulcers
1993, Comparative Biochemistry and Physiology. Part C: Comparative
1. Adrenergic and cholinergic mechanisms seem to be involved in the pathogenesis of stress ulcers.
2. In this study, gastric ulcers were induced in rats by immobilization and cold. Prior intraperitoneal administration of both anticholinergic (atropine) as well as α-blocking medication (phenoxybenzamine) produced a very significant decrease in stress ulcers.
3. Additionally, using the technique of continuous intravenous perfusion in rats, acetylcholine was shown to have a gastric ulcerogenic effect, in contrast to noradrenaline.
4. It is concluded that acetylcholine is the peripheral mediator in stress ulcers, while noradrenaline intervenes at the encephalic level in stress ulcer pathogenesis.

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: This research was supported by NIMH MH-32316, MH-34121, MH-33127 and NICHHD HD-03110.

^**: We are grateful to Debra G. Collins for expert manuscript preparation.

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Involvement of brain dopamine systems on neurotensin-induced protection against stress gastric lesions

Abstract

Physiol. Behav.

J. Biol. Chem.

Brain Res. Bull.

Dev. Brain Res.

Life Sci.

Pharmacol. Biochem. Behav.

Life Sci.

J. Chromatogr.

J. Biol. Chem.

Regul. Peptides

Peptides