Short-term effects of 2,4,5-trihydroxyamphetamine, 2,4,5-trihydroxymethamphetamine and 3,4-dihydroxymethamphetamine on central tryptophan hydroxylase activity.
In previous studies, we have reported the long-term effects of several metabolites of 3,4-methylenedioxymethamphetamine (MDMA) on tryptophan hydroxylase (TPH) activity. In this study, the short-term effects of three metabolites of MDMA. 2,4,5-trihydroxyamphetamine (THA), 2,4,5-trihydroxymethamphetamine (THM) and 3,4-dihydroxymethamphetamine, and the in vitro effect of THA on TPH activity are reported. After short-term treatment, hippocampal TPH activity was decreased to 8 and 54% of control in response to THA and THM, respectively, but was unaltered after 3,4-dihydroxymethamphetamine. Incubating TPH from THM-treated rats with dithiothreitol under nitrogen failed to reverse the decrease in enzyme activity induced by THM treatment. THA also decreased tyrosine hydroxylase activity to 75% of control, whereas the enzyme activity remained unaltered by THM. The structural analog of THA, 6-hydroxydopamine, failed to reproduce the effect of THA on TPH activity; however, 5,6-dihydroxytryptamine decreased hippocampal TPH activity to 18% of control. In the in vitro study, the hippocampus and the striatum were incubated in varying concentrations of THA. After a 1-h incubation at 37 degrees C, hippocampal TPH activity was decreased to 83, 71, 68, 47 and 3% of control after exposure to 0.001, 0.01, 0.1, 0.5 or 5.0 mM THA, respectively; striatal TPH activity was reduced to 98, 95, 70, 54 and 17% of control, respectively. Incubating the enzyme under reducing conditions failed to restore the enzyme activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
I
I
Elayan
J W
JW
Gibb
G R
GR
Hanson
H K
HK
Lim
R L
RL
Foltz
M
M
Johnson
D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014365:Tryptophan Hydroxylase / Q000378:metabolism*
D000662:Amphetamines; C074078:2,4,5-trihydroxymethamphetamine; C074079:2,4,5-trihydroxyamphetamine; C069512:alpha-methylepinine; D008694:Methamphetamine; D016627:Oxidopamine; D014365:Tryptophan Hydroxylase; D003846:Deoxyepinephrine; D015115:5,6-Dihydroxytryptamine