Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species.
Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.
Molecular Neuropsychiatry Section, Cellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA.
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Tsao
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Ladenheim
A M
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Andrews
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Chiueh
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Cadet
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Su
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D009271:Naltrexone / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology
D000975:Antioxidants; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D011957:Receptors, Opioid; D008694:Methamphetamine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D005978:Glutathione