882 Gastric Secretory Studies

The

gastric-acid

contents

([Lmol/h)

were

(mean±SE)

235.0±16.4, 137.8±20.7, and 107.7±16.8 in cysteamine controls and

bromocriptine+cysteamine

and ler-

gotrile+cysteamineBgroups,Brespectively. The4 .molacid output after ligation of the pylorus ([Lmol/h) was also significantly decreased (control, 80.2±13.9) by bromocriptine (34.4±7. 5) or lergotrile (30.9±2.5).

determine whether the effects of bromocriptine, lergotrile, and apomorphine on duodenal ulceration are due

dopamine agonist/antagonist action24 and/or a change in the activity of certain dopamine receptors25 or to

to some

other effect.

I thank Ms H. C. Horner and Mrs K. A. Bailey-Parish for technical help, and the firms which provided drug samples-Sandoz (bromocriptine), Eli & Lilly (lergotrile mesylate), Merck (apomorphine HCI), McNeil (haloperidol and pimozide).

REFERENCES

DISCUSSION

There have been conflicting reports of the effect of

bromocriptine on gastrin and gastric secretion.10," This is probably because although one or two large doses of dopamine agonists aggravate the symptoms and signs of duodenal ulcer, excessive stimulation of dopamine receptors may block the receptor or transform it to antagonist receptor.12," In our present study the anti-ulcerogenic effect of bromocriptine and lergotrile was clearly evident after prolonged treatment and hardly demonstrable after a single dose; similarly prolonged treatment with. either of these two agents is required for Parkinson’s disease. 14,11 The magnitude of the changes in gastric secretion produced by bromocriptine and lergotrile was simithe effect of metiamide and cimetidine in the cysteamine model system.’ Thus, diminished gastric secretion may be at least partly responsible for the antiulcerogenic actions of bromocriptine and lergotrile. Patients with Parkinson’s disease and dopamine receptor supersensitivity have a high incidence of peptic ulcer.16 On the other hand, duodenal ulcers are uncommon17-20 in schizophrenics (who have dopamine excess and/or hyperactivity). These data suggest a high rate of duodenal ulcer in patients with dopamine deficiency and a low incidence in those with probable dopamine excess lar

to

and/or hyperactivity. There is a higher incidence of parkinsonism among persons born during certain years and/or exposed to certain virus infections (e.g., encephalitis lethargica) in certain years (e.g., 1918-1920)21; and the incidence of duodenal ulcer has been dropping in the past decade in the U.S.A. and Western Europe.22 These data raise the question of whether duodenal ulcer is at least partly due to limited exposure to infectious agents or toxic chemicals which impair dopamine production. Further experimental, clinical, and epidemiological studies are needed to settle this question. The mechanism of the beneficial action of dopamine agonists on cysteamine-induced duodenal ulcer is not completely understood. We have previously found an increase in dopamine turnover in the striatum, midbrain, cortex, hypothalamus, and gastric and duodenal mucosa of rats after administration of cysteamine or propioni- trile.23 This increase might be due to secondary (negative feedback) effect of the receptor blockade produced by ulcerogenic chemicals. The aggravation of experimental duodenal ulcers by haloperidol also suggests an inhibition of dopamine receptors. Large doses of propionitrile or cysteamine in these experiments resulted in a biphasic behavioural response-i.e., stereotypy (e.g., sniffing, licking, biting) followed by akinesia and rigidity. Such a response is compatible with dopamine involvement. However, further investigation is required to

1. Szabo S, Selye H. Duodenal ulcers produced by propionitrile in rats. Arch Pathol 1972; 93: 390-91. 2. Selye H, Szabo S. An experimental model for the production of perforating duodenal ulcers by cysteamine in the rat. Nature 1973; 244:458-59. 3. Szabo S. Duodenal ulcer disease. Animal model: cysteamine-induced acute and chronic duodenal ulcer in the rat. Am J Pathol 1978; 93: 273-76. 4. Robert A, Nezamis JE, Lancaster C, Badalamenti JN. Cysteamine-induced duodenal ulcers: A new model to test antiulcer agents. Digestion 1974; 11: 199-214. 5. Ishii Y, Fujii Y, Homma M. Gastric acid stimulating action of cysteamine in the rat. Eur J Pharmacol 1976; 36: 331-36. 6. Borella LE, Seethaler K, Lippmann W. The role of gastric acid and pepsin secretions in the formation of cysteamine-induced duodenal ulcers in rats. In: Mózsik Gy, Jávor T, eds. Progress in Peptic Ulcer. Budapest, Akadé-

miai Kiadó, 1976: 585-96. S, Haith Jr LR, Reynolds ES. Pathogenesis of duodenal ulceration produced by cysteamine or propionitrile. Influence of vagotomy, sympathectomy, histamine depletion, H-2 receptor antagonists and hormones. Am J Dig Dis (Dig Dis Sci) 1979; 24: 471-77. 8. Lichtenberger LM, Szabo S, Trier JS, Reynolds ES. Duodenal ulcerogens,

7. Szabo

propionitrile

and

cysteamine,

stimulate

serum

gastrin

levels in the

rat.

Gastroenterology 1977; 73: 1305-08. 9. Poulsen SS, Szabo S. Mucosal surface morphology and histological changes in the duodenum of the rat following administration of cysteamine. Br J Exp Pathol 1977; 58:1-8. 10. Reding P, De Graef, J, Barbier P. Bromocriptine and gastrin secretion. Lancet 1978; 1:1202-03. 11. Caldara R, Grimaldi D, Ferrari C. Bromocriptine, gastric acid output, and gastrin secretion. Lancet 1977; 1: 902-03. 12. Szabo S. Possible role of brain neurotransmitters and related compounds in the pathogenesis of cysteamine-induced duodenal ulcer. Fed Proc 1976;

36:1019. 13. Enna

SJ, Bennett Jr JP, Burg DR, Creese I, Snyder SH. Stereospecificity of interaction of neuroleptic drugs with neurotransmitters and correlation with clinical potency. Nature 1976; 263: 338-41. 14. Teychenne PF, Calne DB, Lewis PJ, Findley LJ. Interactions of levodopa with inhibitors of monoamine oxidase and L-aromatic amino acid decarboxylase. Clin Pharmacol Ther 1975; 18:273-77. 15. Lieberman A, Kupersmith M, Estey E, Goldstein M. Treatment of Parkinson’s disease with bromocriptine. N Engl J Med 1976; 295: 1400-04. 16. Strang RR. The association of gastro-duodenal ulceration and Parkinson’s disease. Med J Australia 1965; i: 842-43. 17. Pollak OJ, Kreplick F. Peptic ulcers in the insane. Clinical and postmortem study. J Nerve Ment Dis 1945; 101:1- 8. 18. Gosling RH. Peptic ulcer and mental disorder—II. J Psychosom Res 1958; 2:285-301. 19. Samet ET, White MS, Vaughn AM. Duodenal ulcer in a patient with schizophrenia. Am J Dig Dis 1957; 2: 437-41. 20. Hinterhuber H, Hochenegg L. Ulcers, Stress und Schizophrenie Arch Psychiat Nervenker 1975;220: 335-45. 21. Poskanzer DC, Schwab RS, Fraser DW. Further observations on the cohort phenomenon in Parkinson’s syndrome. In: Barbeau A, Brunette JR, eds. Progress in neuro-genetics. Amsterdam; Excerpta Med 1967: 497-505. 22. Sturdevant RAL, Walsh JH. Duodenal ulcer. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal diseases. Philadelphia; W. B. Saunders 1978: 840-60. 23. Szabo S, Horner HC, Bailey KA. Neuropharmacologic and biochemical characterization of chemically-induced duodenal ulcer in the rat. Proc 7th Int Cong Pharmacol Paris 1978: 32. Herrling PL, Burki HR, Asper H, Ruch W. The effect of bromocriptine on rat striatal adenylate cyclase and rat brain monoamine metabolism. J Neurochem 1978; 31: 1163-72. 25. Quik M, Iversen LL. Regional study of 3H-spiperone binding and the dopamine sensitive adenylate cylase in rat brain. Naunyn-Schmiedeberg’s Arch

24. Markstein R,

Pharmacol 1978; 304: 141-49. ADDENDUM

Valenzuela

et

al.

(Gastroenterology, 1979;

76:

323-26)

recently demonstrated an inhibition by dopamine infusion of gastric acid secretion in man. These data seem to accord with our results on dopamine agonists in have

rats.