Cholecystokinin-like immunoreactivity (CCK-LI) and vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) were measured in the brain of Eck fistula dogs and dimethylnitrosamine (DMN)-treated dogs which were prepared as experimental models of hepatic encephalopathy (HE). Significant reduction of CCK-LI was observed in all cortical regions of Eck fistula dogs, especially in parietal and occipital cortex (approximately 40% of control values). In DMN dogs, CCK-LI was reduced in the temporal, parietal and occipital cortex (65%, 47% and 51% of control values, respectively). Significant reduction of VIP-LI was also observed in the occipital cortex of both Eck fistula and DMN dogs (75% and 70% of control values, respectively). These data were compared with the concentrations of tyrosine and phenylalanine, precursors of false neurotransmitters suggested as causing HE. Phenylalanine was significantly increased in all areas of cortex of both models. Tyrosine was also significantly increased in frontal, parietal and occipital cortex of Eck fistula dogs, and in temporal, parietal and occipital cortex of DMN dogs. However, reduced amounts of these peptides did not correlate with increased amounts of the aromatic amino acids in these models. The results imply that reduced levels of CCK and VIP may be elicited by a mechanism distinct from that inducing increase of false neurotransmitters.