The present experiment is undertaken to study the mechanism of the inhibitory effect of 2-pyridylethylamine (PEA, i.c.v.) on the gastric acid secretion. Gastric acid was continuously washed out with 37 degrees C saline by means of a perfusion pump in Wistar rats weighing 200-300 g. Drugs were injected into the third ventricle to examine the effect on pentagastrin-induced (160 micrograms/kg, s.c.) gastric acid secretion. The results were as follows: (1) Pretreatment with naloxone (2.5 micrograms, i.c.v.) blocked the inhibitory effect of PEA (10 micrograms, i.c.v.) on gastric acid secretion. (2) The inhibitory effect of PEA (5-20 micrograms, i.c.v.) was turned into an excitatory effect after subdiaphragmatic vagotomy in a dose-dependent manner, but not changed by bilateral adrenalectomy. (3) In vagotomized rats, pretreatment with CRF-antiserum (1:20,000, 2.5 microliters, i.c.v.) or bilateral adrenalectomy abolished the excitatory effect of PEA (10 micrograms, i.c.v.). (4) PEA (10 micrograms, i.c.v.) did not change the basal gastric acid secretion in vagotomized rats. These results suggest that histamine H1-receptor in brain may be involved in both the inhibitory and excitatory regulation of gastric acid secretion mediated by vagus nerve and the hypothalamus-pituitary-adrenal axis.