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The Journal of Neuroscience, May 28, 2008, 28(22):5756-5761; doi:10.1523/JNEUROSCI.1179-08.2008

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Brief Communications
Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

Yoshimoto Sekine,^1,2 Yasuomi Ouchi,⁴ Genichi Sugihara,⁵ Nori Takei,⁵ Etsuji Yoshikawa,⁶ Kazuhiko Nakamura,² Yasuhide Iwata,² Kenji J. Tsuchiya,⁵ Shiro Suda,² Katsuaki Suzuki,² Masayoshi Kawai,² Kiyokazu Takebayashi,² Shigeyuki Yamamoto,⁵ Hideo Matsuzaki,⁷ Takatoshi Ueki,³ Norio Mori,^2,5 Mark S. Gold,⁸ and Jean L. Cadet¹

¹Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, ²Departments of Psychiatry and Neurology and ³Anatomy and Neuroscience, ⁴Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, ⁵Hamamatsu Center, Osaka-Hamamatsu Joint Research Center for Child Mental Development, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan, ⁶Central Research Laboratory, Hamamatsu Photonics, Hamakita-ku, Hamamatsu, Shizuoka 434-8601, Japan, ⁷Osaka Center, Osaka-Hamamatsu Joint Research Center for Child Mental Development, Suita, Osaka 565-0871, Japan, and ⁸Department of Psychiatry, Division of Addiction Medicine, University of Florida College of Medicine, Gainesville, Florida 32610-0183

Correspondence should be addressed to either Dr. Yasuomi Ouchi or Dr. Jean Lud Cadet, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD 21224, Email: ouchi{at}hama-med.ac.jp or Email: jcadet{at}intra.nida.nih.gov

Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [¹¹C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([¹¹C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [¹¹C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [¹¹C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.

Key words: methamphetamine; addiction; neurotoxicity; microglia; positron emission tomography; human

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Received March 18, 2008; revised May 1, 2008; accepted May 2, 2008.

Correspondence should be addressed to either Dr. Yasuomi Ouchi or Dr. Jean Lud Cadet, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 251 Bayview Boulevard, Baltimore, MD 21224, Email: ouchi{at}hama-med.ac.jp or Email: jcadet{at}intra.nida.nih.gov

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