PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS OBJECTIVE. Our broad goal is to obtain brain imaging data in human methamphetamine (MA) users that could help in development of the vesicular monoamine transporter (VMAT2) as a biomarker to explain pathophysiology and guide clinicians to more appropriate treatment interventions in the drug users. VMAT2 is the synaptic vesicle transporter responsible for monoamine neurotransmitter packaging in human brain, is predominantly localized to dopaminergic terminals in human striatum, and is now proposed in this application as a new tool to investigate vesicular dopamine status in psychostimulant users. BACKGROUND. At present there exists no useful treatment for addiction to the stimulant MA. Although controversial, we believe that a brain deficiency of the neurotransmitter dopamine, as suggested by our postmortem brain findings, might be responsible for some of the behavioural (especially cognitive) problems of MA users. However, in vivo data suggesting dopamine deficiency in MA users are lacking. In a pilot positron emission tomography (PET) study of MA users we discovered, unexpectedly, that striatal (+)- [11C]DTBZ binding to VMAT2 was increased during early abstinence, a finding which can be explained by decreased competition between dopamine (reduced in some MA users) and (+)-[11C]DTBZ binding to VMAT2. As an in vivo biomarker of vesicular dopamine status might be helpful in selecting the most appropriate treatment for MA users, there is need to confirm these findings in a representative number of subjects and establish in a longitudinal study whether binding levels do or do not decline in early abstinence.
SPECIFIC AIM, DESIGN, AND HYPOTHESIS. Our major SPECIFIC AIM is to measure by PET imaging striatal (+)-[11C]DTBZ binding in a representative number of chronic MA users, with each user assessed at 4-7, 12-15, and 28-30 days following last use of the drug, and in a matched control group. Based on our pilot data, our major working HYPOTHESIS is that striatal (+)-[11C]DTBZ binding will be above normal in MA users during very early abstinence (4-7 days) and that levels might normalize in later abstinence (30 days). SIGNIFICANCE. Our study, designed and executed by investigators with extensive VMAT2 expertise in both the human and experimental animal, is a first step aimed at developing a brain biomarker that might identify those MA users who could receive benefit from dopamine substitution medication. In addition, the findings could provide unique information that could help interpretation of brain imaging VMAT2 data in neurology applications for which this biomarker has been proposed to assess efficacy of neuroprotective agents.

Public Health Relevance

This study is aimed at obtaining brain imaging information that will ultimately help in the treatment of patients addicted to the drug methamphetamine. Results might also help in assessing the validity of a brain imaging tool that has been proposed for use in testing whether new neuroprotective drugs slow down the progression of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
4R01DA025096-04
Application #
8428573
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Grant, Steven J
Project Start
2010-03-15
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$198,854
Indirect Cost
$14,730
Name
Centre for Addiction and Mental Health
Department
Type
DUNS #
207855271
City
Toronto
State
ON
Country
Canada
Zip Code
M5S2S-1
Boileau, Isabelle; Payer, Doris; Rusjan, Pablo M et al. (2016) Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users. Neuropsychopharmacology 41:2994-3002
Boileau, Isabelle; McCluskey, Tina; Tong, Junchao et al. (2016) Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence. Neuropsychopharmacology 41:1179-87
Tong, Junchao; Ang, Lee-Cyn; Williams, Belinda et al. (2015) Low levels of astroglial markers in Parkinson's disease: relationship to ?-synuclein accumulation. Neurobiol Dis 82:243-253
Payer, Doris E; Behzadi, Arian; Kish, Stephen J et al. (2014) Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. Neuropsychopharmacology 39:311-8
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Boileau, Isabelle; Payer, Doris; Houle, Sylvain et al. (2012) Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study. J Neurosci 32:1353-9
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Sacher, Julia; Rabiner, Eugenii A; Clark, Michael et al. (2012) Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [(11)C]-harmine positron emission tomography study. J Cereb Blood Flow Metab 32:443-6
Tong, Junchao; Boileau, Isabelle; Furukawa, Yoshiaki et al. (2011) Distribution of vesicular monoamine transporter 2 protein in human brain: implications for brain imaging studies. J Cereb Blood Flow Metab 31:2065-75
Bacher, Ingrid; Houle, Sylvain; Xu, Xin et al. (2011) Monoamine oxidase A binding in the prefrontal and anterior cingulate cortices during acute withdrawal from heavy cigarette smoking. Arch Gen Psychiatry 68:817-26

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