A novel and neurotoxic tetrahydroisoquinoline derivative in vivo: formation of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, a condensation product of amphetamines, in brains of rats under chronic ethanol treatment.
Repeated amphetamine administration to rats under chronic ethanol intoxication resulted in the formation of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (1,3-DiMeTIQ), a novel metabolite of amphetamines. 1,3-DiMeTIQ was quantified with a sensitive, specific assay using gas chromatography-mass spectrometry. It was not found in the brains of rats given repeated amphetamine administration but no ethanol. The chronic ethanol-intoxicated rats subjected to repeated amphetamine administration exhibited behavioral abnormalities, such as repeated convulsions and curving of the back. 1,3-DiMeTIQ contents were markedly higher in the brain or plasma of rats manifesting abnormal behavior in comparison with those in rats behaving normally. Thus, the 1,3-DiMeTIQ content in the rat brain seems to have some relationship with behavioral abnormalities. This study also confirmed that 1,3-DiMeTIQ can cross the blood-brain barrier in the rat. Intraperitoneal 1,3-DiMeTIQ injections to rats caused behavioral symptoms similar to those observed in rats with chronic ethanol intoxication and repeated amphetamine administration. The effect of toxic doses of 1,3-DiMeTIQ on dopaminergic and serotonergic metabolism in the whole rat brain was also investigated.
Makino
Y
Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Ohta
S
S
Tasaki
Y
Y
Tachikawa
O
O
Kashiwasake
M
M
Hirobe
M
M
D000437:Alcoholism / Q000378:metabolism; D000662:Amphetamines / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D044005:Tetrahydroisoquinolines
D000662:Amphetamines; D001679:Biogenic Amines; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C065331:1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; D012701:Serotonin; D000431:Ethanol; D004298:Dopamine