Tryptophan-related Neurotransmission in the Brain: Disturbances Associated with Experimental Hepatic Encephalopathy

Sammanfattning: In the present study, L-tryptophan (TRP)-related disturbances in the brain in experimental hepatic encephalopathy (HE) were investigated. The endogenous NMDA-receptor agonist and L-TRP metabolite quinolinic acid (QUIN) has been suggested to be involved in the pathogenesis of HE. We were, however, unable to detect any increases in QUIN levels in rats subjected to a chronic portacaval shunt (PCS) either in plasma, brain tissue, or brain extracellular fluid. Furthermore, administration of ammonium acetate (NH4Ac) or L-TRP did not result in any difference in QUIN levels between PCS and sham-operated rats. The other main part of the actual study concerned investigations on the release of serotonin (5-HT) in the brain in HE. Despite a previously evidenced profound increase in brain metabolism of 5-HT in experimental HE, the neocortical release of 5-HT was found not to be changed in this situation. Challenges with L-TRP did not mainly affect the brain 5-HT release in either sham or PCS. NH4Ac administration caused a transient increase in brain 5-HT release of PCS rats during a time-period at which these rats were in a state of reversible coma. KCl provocation also resulted in clear elevations of the 5-HT output of PCS rats compared with matched controls. No difference in the 5-HT response to a d-fenfluramine (dFEN) administration was seen between sham and PCS rats. A clear difference in brain 5-HT release was, however, observed following p-chloroamphetamine (pCA) perfusion possibly indicating a larger extravesicular pool of 5-HT in PCS rats than in the brains of the sham-operated controls. In a final study, differences in pharmacodynamics as well as pharmacokinetics for the serotonin reuptake inhibitor citalopram were observed between PCS and sham. It is concluded that QUIN is not involved to any major extent in the pathogeneis of HE. The basal brain 5-HT release in not altered in experimental chronic PSE but an augmented neocortical 5-HT release compared with the normal in vivo situation is available under certain conditions. Based on these data a more restrictive use for e.g. potent novel 5-HT-acting drugs should be advocated in patients suffering from liver dysfunction and pending HE.