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Animals with a portacaval shunt exhibit several biochemical abnormalities in plasma and brain similar to patients with portal-systemic encephalopathy, i.e., hyperammonemia, amino acid imbalance, and neurotransmitter disturbances. We investigated behavior and brain monoamine metabolism in operated, sham-operated, and nonoperated rats 1 day and 2, 4, and 6 weeks after operation. In order to quantitate the turnover in the brain indoleamine and catecholamine systems, 5-hydroxytryptophan (5-HTP) and dihydroxyphenylalanine were measured after decarboxylase inhibition with NSD 1015. The brains were dissected into five regions. All rats with the shunt had high plasma ammonia concentrations. Behavioral tests revealed a reduction in spontaneous locomotion 2, 4, and 6 weeks after portacaval shunt and reduced exploratory behavior compared with control rats. These changes coincided with profound alterations of the indoleaminergic system. As early as 1 day after surgery, rats with the shunt showed a marked increase in the accumulation of 5-HTP in all brain regions, indicating an enhanced tryptophan hydroxylase activity. The changes in indoleamine synthesis were most profound in the cortex and the midbrain. Only minor alterations of the catecholaminergic system could be detected. The alterations in behavior and indoleamine neurotransmitter metabolism may be pathophysiologically interrelated and may serve as the basis for experimental studies of portal-systemic encephalopathy.