Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats

Abstract

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.

Introduction

Gastric ulcer is the most prevalent gastrointestinal disorder and has been a major health problem with a high rate of global incidence. Several factors are known to influence the pathogenesis of gastric ulcer formation and an imbalance between ‘aggressive’ and ‘defensive’ forces may result in the loss of gastric mucosal integrity (Hoogerwerf and Pasricha, 2006). Among various ulcerogenic factors, the stress-induced gastric ulceration is proposed to be mediated by corticotrophin releasing factor (CRF) (Bhatia and Tandon, 2005), corticosteroids (Mayer, 2000), prostaglandins (Dharmani et al., 2005) acid secretion (Hoogerwerf and Pasricha, 2006) and neurotransmitters (Saad et al., 2001). Understanding the intricate relationships between gastric ulcers and stress mediators (such as corticosterone, CRF, prostaglandins, dopamine) under different stressful conditions is crucial, as the patients suffering from shock, sepsis, severe trauma, or head injury can develop acute erosive gastric mucosal changes or frank ulceration with bleeding, which are life threatening (Hoogerwerf and Pasricha, 2006, Valle, 2008).

It is well documented that dopaminergic system plays an important regulatory role in stress-induced gastric ulcers (Glavin, 1991). Interestingly, in Parkinson's disease the onset of gastric lesions becomes fast supposedly due to the deficiency of dopamine, where as in Schizophrenia, incidence of gastric lesions are lowered possibly due to a high concentration of dopamine this emphasized a link between the dopamine concentration and gastric ulcer pathology (Mayer, 2000). The gastric cytomodulatory effects are associated with the modulation of dopaminergic transmission by specific dopamine drugs (Sikiric et al., 1986). Dopamine influences the gastric cytoprotective effects of other neurotransmitters (Ray et al., 1987). Although previous studies suggested the selective activation of the mesocorticolimbic dopamine systems in stress-induced ulcers (Henke, 1979), the involvement of gastric mucosal dopaminergic alterations during such stressful conditions is largely unknown. It is reported that dopamine receptors influence the hypothalamic–pituitary–adrenal response (Van Craenenbroeck et al., 2005), which may lead to enhanced corticosteroid levels, also known to modulate gastric glands to secrete acid and pepsin (Gray et al., 1951). Thus, understanding the relationship between corticosteroids and dopaminergic system may further provide insights into the biological basis of stress-induced ulcers. Reports indicated an enhancement in prostaglandin formation in gastric mucosa by dopamine agonists suggesting their role in cytoprotection during stress (Ray et al., 1990). Further, PGE₂ is reported to be involved in the process of ulcer healing (Dharmani et al., 2005). Thus, it is essential to understand the intricate relationship between dopaminergic and PGE₂ systems, specifically in the gastric mucosal tissue.

A 68930, a potent selective D1 agonist, alters the stress-related grooming, stereotypic and vacuous chewing behaviour (Salmi and Ahlenius, 2000). However, its role in stress ulcers is largely unknown. Other dopamine receptor drugs such as SCH 23390 and quinpirole are mostly used to delineate the involvement of dopamine in locomotion and other behavioral functions (Neisewander et al., 1998, Foley et al., 2006). Sulpiride is reported to have ulcerogenic and gastroprotective effects at lower and higher doses, respectively (Ray et al., 1990). Nevertheless, there are only a few reports, which indicated the involvement of dopamine receptor subtypes in the onset of gastric ulcers in experimental animals (Sikiric et al., 1986, Desai et al., 1999). None of these reports has addressed the evaluation of specific role of dopaminergic transmission in relation to the changes in gastric mucosal dopamine levels and its receptor stimulation under differential stressful conditions. Furthermore, the effect of dopaminergic system in gastric mucosa with other ulcerogenic factors such as corticosteroids, acid secretion (proton pump), PGE₂ levels and consequent histopathological changes warrants further study.

Here, we have shown for the very first time the relationship of dopamine with gastric ulcer formation in different stressful conditions in rats. In this regard, our finding address following two issues. Firstly, to characterize the involvement of selective dopamine receptor agonists and antagonists during acute and chronic unpredictable stress, the changes in gastric ulcer severity, adrenal hypertrophy and plasma corticosterone levels were examined. It is well perceived that gastric ulcerogenesis is not a simple consequence of stress; and a number of factors possibly governing through dopamine are involved. Thus, our second issue was to evaluate the involvement of peripheral dopamine system on stress-induced ulcers by measuring the simultaneous changes in the gastric mucosal dopamine levels and its influence on other ulcerogenic factors following the treatment of dopamine receptor agonists and antagonists. Hence, parallel perturbations in systems like corticosteroids, proton pump activity, gastric mucosal PGE₂ levels and histopathological alterations were examined under similar conditions.