Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users

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Abstract

We measured levels of methamphetamine and those of its metabolite amphetamine in 15 autopsied brain regions of 14 human methamphetamine users. Only slight regional differences were observed in drug concentrations among the brain areas. Although, some redistribution of the drugs probably occurred postmortem, these data suggest that methamphetamine might not be preferentially retained in dopamine-rich brain areas but is heterogenously distributed in brain of chronic human users of the drug. The possible pharmacological actions of methamphetamine in both dopamine-rich and poor brain areas of chronic drug users need to be considered.

Introduction

It is now well established that the mechanism of the euphoric action of methamphetamine and its metabolite amphetamine is related to the ability of recreational doses of the abused drugs to enter dopamine nerve terminals in the striatum (caudate, putamen, nucleus accumbens) and cause release of the neurotransmitter dopamine [1]. Much higher drug doses can produce in experimental animals long lasting damage to dopamine nerve terminals in striatum with a sparing of the cell bodies [2]. However, whether such toxic damage occurs in human methamphetamine users and is restricted to striatal dopamine neurones remains to be established [3], [4].

Although, most interest in methamphetamine has focussed on its actions in the dopamine-rich striatal brain area, levels of methamphetamine are relatively uniformly distributed throughout the brain of experimental animals administered a single dose of the drug (cf. [5], [6], [7]). However, methamphetamine uptake has also been reported to be higher in striatum versus other brain areas of chronically treated animals [8]. Furthermore, retention of amphetamine in striatum is decreased in animals who have had lesion of dopamine neurones [5]. This suggests that some preferential storage and retention of methamphetamine might occur in dopamine nerve terminal-rich areas of the brain such as the striatum.

To our knowledge, no information is available with respect to the regional distribution of methamphetamine in brain of human users of the drug. Information on the distribution of the drug in human brain is important in view of the possibility that methamphetamine might damage neurones in both dopamine-rich striatal and dopamine-poor extra-striatal brain areas. In the present investigation we directly measured concentrations of methamphetamine and its metabolite amphetamine in 15 postmortem brain areas of 14 human chronic methamphetamine users. Our cases selected were those who spanned a wide range of brain drug concentrations. We report that methamphetamine is homogeneously distributed within the brain of chronic human users of the drug with only slight differences among the examined brain areas.

Section snippets

Methamphetamine users

Postmortem brain material from a total of 14 methamphetamine users was obtained from medical examiner offices in the US drug history, brain neuropathological findings and results of toxicological analyses of methamphetamine and amphetamine in blood and in one autopsied brain area (caudate nucleus) of 12 of the 14 methamphetamine users have been previously reported [3]. Cases were included for study if toxicological analysis indicated the presence of methamphetamine in blood. A standardized

Subject characteristics

Table 1 shows the ages, postmortem intervals (interval between death and freezing of the half-brain at −80°C), sex, estimate of the duration of drug use from the clinical case histories and the suspected (drug intoxication) or known (gunshot wound) cause of death. As shown in Table 1, methamphetamine intoxication was the suspected cause of death in 10 of the 14 methamphetamine users. The suspected or known causes of death of the remaining subjects were cardiovascular disease with

Discussion

The major finding of our investigation is that concentrations of methamphetamine show little variation among brain regions of chronic users of the drug.

Methamphetamine is metabolized in the body by N-demethylation to amphetamine, which further metabolizes by oxidation to norephedrine. All three forms are psychoactive and each undergoes further metabolism by hydroxylation, deamination and/or conjugation to non-active metabolites. Approximately 45% of the ingested methamphetamine is excreted from

Acknowledgements

This study was supported by US NIH NIDA DA 07182 to SK. The authors thank the American Registry of Pathology for their support of this project.

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The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting views of the United States Department of Army or Department of Defence.

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