Long-Term Protective Effects of Methamphetamine Preconditioning Against Single-Day Methamphetamine Toxic Challenges

A B Hodges,J L Cadet,N Cai,M T Mccoy,I N Krasnova,B Ladenheim,G Beauvais

doi:10.2174/157015911795017344

Abstract

Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH –induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems.

Highlights

Methamphetamine (METH) use is a global epidemic because it has become easier to synthesize and administer [1, 2]
The main finding of the present paper is that METH preconditioning can protect against the long-term biochemical effects of a toxic dose of the drug
The protective effects of METH pretreatment were observed in animals killed 14 days after the METH challenge

Summary

Introduction

Methamphetamine (METH) use is a global epidemic because it has become easier to synthesize and administer [1, 2]. METH causes neurodegenerative changes in the brains of human addicts including decreases in the density of striatal dopamine transporter (DAT) [5, 6] and serotonin transporter (SERT) [7] observed in positron emission tomography (PET) studies. METH-induced neurodegenerative effects have been studied extensively using animal models. These abnormalities include depletion of DA and its metabolites, 3,4dihyroxyphenylacetic acid (DOPAC) and homovallic acid (HVA) levels, DAT density in the striatum and nucleus accumbens [9], decreases in the levels of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), SERT density [10] as well as cell death via activation of apoptotic pathways [11,12,13]

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Conclusion