It has been previously shown that long-term treatment with low doses of L-sulpiride is highly effective in rat models of depression and of anticipatory anxiety/panic behavior. The present study was aimed at investigating whether the same treatment can prevent the ulcerogenic effect of repeated inescapable stresses. In adult rats, the repeated (7 consecutive days) exposure to an uncontrollable stressful condition (inescapable 2.5 mA scrambled shock for 60 s) produced the development of gastric lesions (multiple punctiform telangiectasias in all rats, with superficial erosions or more severe ulcerations in 10 out 13 rats; score 4.67 +/- 0.44). L-sulpiride, intraperitoneally injected once a day at an antidepressant dose level (4 mg kg(-1) per day), starting 21 days before the beginning of the 7-day sequence of inescapable punishments (= 28 daily treatments), almost completely prevented the stress-induced gastric injury (score 1.67 +/- 0.29; P < 0.001 vs saline-treated rats, Mann-Whitney U test). These results show that, in rats, a long-term treatment with low doses of L-sulpiride prevents the development of gastric lesions induced by chronic exposure to uncontrollable stress. (C) 2000 Academic Press.