Several novel arylpiperazine serotonin 1A receptor agonists, developed as anxiolytics, have antisecretory and gastroprotective effects in rats. E4424 (2-¿4-[4-(4-chloropyrazol-1-yl)butyl]-1-piperazinyl ¿pyrimidine; Lesopitron dihydrochloride), has potent anti-gastric secretory and antiulcer effects. Preliminary data indicated an enhancing effect of E4424 on gastric mucus that may underlie its gastroprotective actions. We therefore tested the effects of acute and chronic administration of E4424 and of a reference 5-HT1A receptor agonist, 8-OHDPAT [8-hydroxy-2-(di-n-propylamino)tetralin], on gastric mucus levels in rats subjected to cold-restraint stress, a procedure associated with depletion of gastric mucus and the development of mucosal injury. Acute oral administration of E4424 increased adherent mucus levels by 12%, 11%, and 13%, relative to controls. Chronic E4424 significantly increased gastric mucus relative to controls (69% increase). Acute oral treatment with 8-OHDPAT did not affect gastric mucus level. Acute intraperitoneal 8-OHDPAT slightly increased mucus levels. Chronic twice per day 8-OHDPAT did not affect mucus levels; however, chronic once per day treatment with 8-OHDPAT significantly elevated gastric mucus levels at the highest doses used. For E4424, there is a strong correlation between reduction of gastric mucosal injury and increase in gastric mucus level, suggesting that the action of E4424 on glandular mucus levels is an important mechanism underlying its gastroprotective effects.