Absence of 6-hydroxydopamine in the rat brain after treatment with stimulants and other dopaminergic agents: a mass fragmentographic study.
Formation of 6-hydroxydopamine (6-OHDA) from dopamine has been hypothesized to mediate neurodegeneration induced by some psychostimulants. Although the emergence of a 6-OHDA-like substance was reported in the striatum of methamphetamine-treated rats, this substance has not been identified by a direct approach. We used mass fragmentography to search for 6-OHDA in the rat frontal cortex and striatum after the administration of a number of drugs including 3,4-dihydroxyphenyl-L-alanine, methamphetamine, amphetamine, and cocaine, all of which increase synaptic dopamine. No 6-OHDA was detected after the acute systemic administration of these agents. Intraventricular administration of 6-OHDA (10 micrograms/rat) produced measurable concentrations of 6-OHDA that were higher in the striatum than in the frontal cortex. Intraventricular administration of 2,4,5-trihydroxyphenyl-D,L-alanine (6-OHDOPA; 10 micrograms/rat) produced similar concentrations of 6-OHDA in both regions. Pargyline, but not carbidopa (alpha-methyl-dopa-hydrazine), enhanced the effect of intraperitoneal 6-OHDOPA administration (80 mg/kg). We conclude that (1) 6-OHDOPA can cross the blood-brain barrier and is converted to 6-OHDA in the brain, (2) 6-OHDA is a substrate for monoamine oxidase(s) and therefore a search for its purported deaminated metabolite is warranted, and (3) acute treatment with the above stimulants either does not lead to the formation of 6-OHDA or produces concentrations below the detection limit of the assay (< 34 pg/mg of protein).
Karoum
F
F
Neuropsychiatry Branch, Intramural Research Program, National Institute of Mental Health, Neuroscience Research Center, Washington, D.C. 20032.
Chrapusta
S J
SJ
Egan
M F
MF
Wyatt
R J
RJ
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002230:Carbidopa / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D004338:Drug Combinations; D004355:Drug Stability; D005625:Frontal Lobe / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D007276:Injections, Intraventricular; D008297:Male; D016627:Oxidopamine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical
D015259:Dopamine Agents; D004338:Drug Combinations; C001388:6-hydroxydopa; D004295:Dihydroxyphenylalanine; D016627:Oxidopamine; D010293:Pargyline; D002230:Carbidopa