Evidence for a serotonin transporter deficit in experimental acute liver failure.
It has been suggested that alterations of serotonin transport may be implicated in the pathogenesis of the neuropsychiatric symptoms encountered in acute liver failure. In order to address this issue, microdialysate concentrations of serotonin, its precursor L-tryptophan and metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as brain regional distribution of serotonin transporter ([3H]-citalopram) sites were measured in rats with acute liver failure resulting from hepatic devascularization. A significant loss of [3H]-citalopram sites was observed in dorsal Raphe nucleus, in frontal and frontoparietal cortices as well as in substantia nigra of rats with severe encephalopathy resulting from acute liver failure. In frontal cortex, this loss of transporter binding sites was accompanied by significant increases of L-tryptophan, serotonin and 5-HIAA concentrations in extracellular fluid. Pharmacological manipulation of the brain serotonin system could afford a novel therapeutic approach to the prevention of the neuropsychiatric symptoms characteristic of acute liver failure in humans.
Michalak
A
A
Neuroscience Research Unit, CHUM Hôpital Saint-Luc, University of Montreal, 1058 St. Denis Street, Montreal, Que., Canada H2X 3J4.
Chatauret
N
N
Butterworth
R F
RF
D000208:Acute Disease; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins; D015283:Citalopram / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000503:physiopathology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007511:Ischemia / Q000150:complications; D008102:Liver Circulation; D017093:Liver Failure / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D014018:Tissue Distribution; D014364:Tryptophan / Q000378:metabolism
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D015283:Citalopram; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan