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The Journal of Neuroscience, September 24, 2008, 28(39):9850-9856; doi:10.1523/JNEUROSCI.3008-08.2008

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Neurobiology of Disease
Increased Vesicular Monoamine Transporter Binding during Early Abstinence In Human Methamphetamine Users: Is VMAT2 a Stable Dopamine Neuron Biomarker?

Isabelle Boileau,¹ Pablo Rusjan,² Sylvain Houle,² Diana Wilkins,⁴ Junchao Tong,¹ Peter Selby,³ Mark Guttman,^1,2,3,4,5,6 Jean A. Saint-Cyr,⁵ Alan A. Wilson,² and Stephen J. Kish¹

¹Human Neurochemical Pathology Laboratory, ²Vivian M. Rakoff PET Imaging Centre, and ³Addictions Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada M5T 1R8, ⁴Center for Human Toxicology, University of Utah, Salt Lake City, Utah 84101, ⁵Division of Brain Imaging and Behavior Systems, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 2M9, and ⁶Centre for Movement Disorders, Markham, Ontario, Canada L6B 1C9

Correspondence should be addressed to Dr. Isabelle Boileau, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Email: isabelle_boileau{at}camh.net

Animal data indicate that methamphetamine can damage striatal dopamine terminals. Efforts to document dopamine neuron damage in living brain of methamphetamine users have focused on the binding of [¹¹C]dihydrotetrabenazine (DTBZ), a vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, as a stable dopamine neuron biomarker. Previous PET data report a slight decrease in striatal [¹¹C]DTBZ binding in human methamphetamine users after prolonged (mean, 3 years) abstinence, suggesting that the reduction would likely be substantial in early abstinence. We measured striatal VMAT2 binding in 16 recently withdrawn (mean, 19 d; range, 1–90 d) methamphetamine users and in 14 healthy matched-control subjects during a PET scan with (+)[¹¹C]DTBZ. Unexpectedly, striatal (+)[¹¹C]DTBZ binding was increased in methamphetamine users relative to controls (+22%, caudate; +12%, putamen; +11%, ventral striatum). Increased (+)[¹¹C]DTBZ binding in caudate was most marked in methamphetamine users abstinent for 1–3 d (+41%), relative to the 7–21 d (+15%) and >21 d (+9%) groups. Above-normal VMAT2 binding in some drug users suggests that any toxic effect of methamphetamine on dopamine neurons might be masked by an increased (+)[¹¹C]DTBZ binding and that VMAT2 radioligand binding might not be, as is generally assumed, a "stable" index of dopamine neuron integrity in vivo. One potential explanation for increased (+)[¹¹C]DTBZ binding is that VMAT2 binding is sensitive to changes in vesicular dopamine storage levels, presumably low in drug users. If correct, (+)[¹¹C]DTBZ might be a useful imaging probe to correlate changes in brain dopamine stores and behavior in users of methamphetamine.

Key words: vesicular monoamine transporter 2; positron emission tomography; dihydrotetrabenazine; methamphetamine; dopamine; monoamine

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Received June 30, 2008; accepted Aug. 15, 2008.

Correspondence should be addressed to Dr. Isabelle Boileau, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Email: isabelle_boileau{at}camh.net

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