Delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin causes a near completeblockade of the neuronal damage induced by a single high dose of methamphetamine: Examining the role of p53

The delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been re ported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). We examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice, The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic a cid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content ( a similar to 50% blockade). DADLE did not affect the changes of rectal temp erature induced by the administration of the high dose of METH, METH increa sed p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE aboli shed the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked b oth the increase of p53 mRNA and the decrease of p53 protein caused by METH . These results demonstrate a neuroprotective effect of DADLE against the n euronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance betwe en the protein level of p53 and the neurotoxicity caused by a high dose of METH. Synapse 39:305-312, 2001, Published 2001 Wiley-Liss, Inc.dagger.