Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced brain serotonin metabolism in the rat.
It has previously been shown that a lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the brain concentrations of serotonin precursor, tryptophan, and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in TCDD-susceptible Long-Evans but not in TCDD-resistant Han/Wistar rats. In the present study, TCDD (50 micrograms/kg; LD100 for Long-Evans and nonlethal for Han/Wistar rats) enhanced de novo biosynthesis of serotonin in the brain of Long-Evans but not Han/Wistar or food-restricted Long-Evans rats 10 days after exposure. Furthermore, TCDD increased the plasma level of free tryptophan in Long-Evans rats alone, which may be causally related to the observed effects of TCDD on brain tryptophan levels. Administration of hemin modified the time course of TCDD-induced anorexia although 10 day cumulative food consumption was not altered. Hemin tended to attenuate TCDD-elicited increases in brain serotonin turnover, whereas a beta-adrenergic blocker, propranolol, did not. In the majority of Long-Evans rats, TCDD inhibited the main tryptophan degrading enzyme in the liver, tryptophan pyrrolase, but the rest exhibited augmented activities; these effects were not altered by hemin. TCDD increased the plasma levels of nonesterified fatty acids in Long-Evans (five-fold) but not in Han/Wistar rats. A slight elevation (two-fold) was also seen in food-restricted Long-Evans rats. It is concluded that TCDD selectively promotes brain serotonin turnover in Long-Evans rats and this acceleration is related to increased plasma levels of free tryptophan. The inhibition of tryptophan catabolism in the liver and elevation of plasma nonesterified fatty acids may contribute to these changes.
Unkila
M
M
National Public Health Institute, Department of Toxicology, Kuopio, Finland.
Pohjanvirta
R
R
MacDonald
E
E
Tuomisto
J
J
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity; D014364:Tryptophan / Q000097:blood / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D018377:Neurotransmitter Agents; D000072317:Polychlorinated Dibenzodioxins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D011433:Propranolol; C004297:3-hydroxybenzylhydrazine; D014366:Tryptophan Oxygenase