Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.
Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.
Gibb
J W
JW
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Bush
L
L
Hanson
G R
GR
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008694:Methamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D012701:Serotonin; D008694:Methamphetamine; D014365:Tryptophan Hydroxylase; D008550:Melatonin; D004298:Dopamine