Abstract
Animal studies suggest that the widely used psychostimulant drug methamphetamine (MA) can harm brain dopamine neurones, possibly by causing oxidative damage. However, evidence of oxidative damage in brain of human MA users is lacking. We tested the hypothesis that levels of two “gold standard” products generated from lipid peroxidation, 4-hydroxynonenal (one of the most reactive lipid peroxidation aldehyde products) and malondialdehyde, would be elevated in post mortem brain of 16 dopamine-deficient chronic MA users compared with those in 21 matched control subjects. Derivatized aldehyde concentrations were determined by gas chromatography-mass spectrometry. In the MA group, we found significantly increased levels of 4-hydroxynonenal and malondialdehyde in the dopamine-rich caudate nucleus (by 67 and 75%, respectively) and to a lesser extent in frontal cortex (48 and 36%, respectively) but not in the cerebellar cortex. Approximately half of the MA users had levels of 4-hydroxynonenal falling above the upper limit of the control range in caudate and frontal cortex. A subgroup of MA users with high brain drug levels had higher concentrations of the aldehydes. Our data suggest that MA exposure in human causes, as in experimental animals, above-normal formation of potentially toxic lipid peroxidation products in brain. This provides evidence for involvement of oxygen-based free radicals in the action of MA in both dopamine-rich (caudate) and -poor (cerebral cortex) areas of human brain.
Footnotes
-
This work was supported by the National Institute on Drug Abuse/National Institutes of Health Grant DA07182 and by the New Zealand Institute of Environmental Science and Research, Ltd.
-
The assertions and opinions 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 Defense.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.109173.
-
ABBREVIATIONS: MA, methamphetamine; HNE, 4-hydroxynonenal; HNE(d11), trans-4-hydroxy-nonenal-5,5,6,6,7,7,8,8,9,9,9-d11; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substances; PMI, post mortem interval; GC, gas chromatography; MS, mass spectrometry; TMS, trimethylsilyl; ANCOVA, analysis of covariance; HPLC, high-performance liquid chromatography; PFB, 2,3,4,5,6-pentafluoro-benzyl.
- Received June 7, 2006.
- Accepted July 18, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|