MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abstract

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.

• Authors: A Keshavarzian, A Wibowo, J H Gordon, J Z Fields
• Journal: Gastroenterology (Gastroenterology) Vol. 98 Issue 3 Pg. 554-60 (Mar 1990) ISSN: 0016-5085 [Print] United States
• PMID: 2298362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dopamine Antagonists
• Monoamine Oxidase Inhibitors
• Serotonin Antagonists
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Norepinephrine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (administration & dosage)
• Animals
• Dopamine Antagonists
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Drug Interactions
• Duodenal Ulcer (chemically induced, prevention & control)
• Female
• MPTP Poisoning
• Monoamine Oxidase Inhibitors (therapeutic use)
• Norepinephrine (antagonists & inhibitors)
• Rats
• Rats, Inbred F344
• Serotonin Antagonists (therapeutic use)
• Time Factors