alpha-Methyl-p-tyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation.
Depletion of brain dopamine (DA) by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMT) has been shown to prevent the long-term neurotoxic effects of methamphetamine (MA). In addition, it has recently been reported that the neurotoxins 6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed endogenously in neostriatum and hippocampus, respectively, following a single neurotoxic dose of MA. We, therefore, have examined the ability of AMT pretreatment to prevent the MA-induced formation of 6-OHDA and 5,6-DHT. We report that AMT pretreatment significantly decreases the frequency with which 6-OHDA and 5,6-DHT are detected following MA administration. Neurotoxin formation is compared with brain levels of DA and 5-hydroxytryptamine (5-HT) 2 weeks after MA administration. It is concluded that the ability of AMT to attenuate both 6-OHDA formation and long-term depletions of DA is due to a decrease in the MA-releasable pool of DA. The effect of AMT on MA-induced depletions of 5-HT is less clear and may involve additional factors.
Axt
K J
KJ
Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.
Commins
D L
DL
Vosmer
G
G
Seiden
L S
LS
D015115:5,6-Dihydroxytryptamine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006892:Hydroxydopamines / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008781:Methyltyrosines / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D019805:alpha-Methyltyrosine
D006892:Hydroxydopamines; D008781:Methyltyrosines; D009498:Neurotoxins; D008694:Methamphetamine; D019805:alpha-Methyltyrosine; D016627:Oxidopamine; D004298:Dopamine; D015115:5,6-Dihydroxytryptamine