Addiction Imaging Research Group

Toronto, Canada

Addiction Imaging Research Group

Toronto, Canada
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Boileau I.,Addiction Imaging Research Group | Boileau I.,Vivian koff Pet Imaging Center | Boileau I.,Center for Addiction and Mental Health | Boileau I.,University of Toronto | And 28 more authors.
Journal of Neuroscience | Year: 2012

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior.Wetested the hypothesis thatD3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [ 11C]-(+)-propyl-hexahydro-naphthooxazin ([ 11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [ 11C]-(+)-PHNO. Compared with control subjects, drug users had higher [ 11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN;+46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately-4%, NS;-12% in heavy users, p = 0.01) and related to drug-use severity. The [ 11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p = 0.004), with heavy but not moderate users having ratios significantly different from controls. [ 11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse. © 2012 the authors.

Tong J.,Addiction Imaging Research Group | Furukawa Y.,Movement Disorders Research Laboratory | Furukawa Y.,Juntendo University | Sherwin A.,McGill University | And 2 more authors.
Neurobiology of Disease | Year: 2011

There is much controversy regarding the extent of axon regeneration/sprouting ability in adult human brain. However, intrinsic differences in axon/neurite growth capability amongst striatal (caudate, putamen, nucleus accumbens) subdivisions could conceivably underlie, in part, their differential vulnerability in degenerative human brain disorders. To establish whether the distribution of axon growth markers in mature human striatum might be uniform or heterogeneous, we measured the intra-striatal pattern, in autopsied brain of normal subjects (n= 40, age 18-99), of proteins involved in regulating axon growth. These proteins included polysialylated neural cell adhesion molecule (PSA-NCAM), microtubule-associated proteins TUC-4 (TOAD/Ulip/CRAMP-4) and doublecortin (DCX), and Bcl-2. The distribution of the marker proteins within the striatum was heterogeneous and inversely related to the pattern of dopamine loss previously characterized in Parkinson's disease (PD), with levels in nucleus accumbens > caudate > putamen, ventral > dorsal, and rostral putamen > caudal. In contrast, distribution of glial markers including glial fibrillary acidic protein (GFAP) and human leukocyte antigens (HLA-DRα and HLA-DR/DQ/DPβ), other Bcl-2 family proteins, and control proteins neuron-specific enolase and α-tubulin in the striatum was either homogeneous or had a pattern unmatched to dopamine loss in PD. The putamen also showed more marked age-dependent decreases in concentrations of PSA-NCAM, TUC-4, and DCX and increases in GFAP levels than caudate. We conclude that the intrastriatal pattern of several key axon growth proteins is heterogeneous in adult human brain. Further investigation will be required to establish whether this pattern, which was inversely correlated with the pattern of dopamine loss in PD, is involved to any extent in the pathophysiology of this degenerative disorder. © 2010 Elsevier Inc.

Payer D.,Addiction Imaging Research Group | Payer D.,Campbell Family Mental Health Institute | Payer D.,Research Imaging Center | Payer D.,Center for Addiction and Mental Health | And 7 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2014

The chronic use of drugs, including psychostimulants such as cocaine and amphetamine, has been associated with low D2/3 dopamine receptor availability, which in turn has been linked to poor clinical outcome. In contrast, recent studies focused on the D3 receptor (a member of the D2-like receptor family) suggest that chronic exposure to stimulant drugs can up-regulate this receptor subtype, which, in preclinical models, is linked to dopamine system sensitization - a process hypothesized to contribute to relapse in addiction. In this mini review we present recent human data suggesting that the D3 receptor may contribute to core features of addiction, and discuss the usefulness of the PET imaging probe [11C]-(+)-PHNO in investigating this question. © 2013 Elsevier Inc.

Tong J.,Center for Addiction and Mental Health | Tong J.,Addiction Imaging Research Group | Meyer J.H.,Research Imaging Center | Furukawa Y.,Juntendo University | And 6 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2013

Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: [11C]harmine, [11C]clorgyline, and [11C] befloxatone; MAO-B: [11C]deprenyl-D2) has been actively pursued given clinical importance of MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n=38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of [11C]befloxatone (binding potential (BP), r=0.61, P=0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P<0.01) for [11C]harmine (distribution volume, r=0.86), [ 11C]clorgyline (λk3, r=0.82), and [ 11C]deprenyl-D2 (λk3 or modified Patlak slope, r=0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ~2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality. © 2013 ISCBFM All rights reserved.

Tong J.,Center for Addiction and Mental Health | Tong J.,Addiction Imaging Research Group | Boileau I.,Addiction Imaging Research Group | Furukawa Y.,Juntendo University | And 5 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter 100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects. © 2011 ISCBFM All rights reserved.

Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,University of Toronto | Collo G.,University of Brescia | And 5 more authors.
Progress in Brain Research | Year: 2014

The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction. © 2014 Elsevier B.V.

Boileau I.,Addiction Imaging Research Group | Boileau I.,Vivian koff Pet Imaging Center | Boileau I.,Center for Addiction and Mental Health | Boileau I.,University of Toronto | And 23 more authors.
Molecular Psychiatry | Year: 2014

Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D 3 receptor-preferring radioligand [11 C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [11 C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D 3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D 3 -related mechanisms might contribute to the pathophysiology of behavioral addictions. © 2014 Macmillan Publishers Limited.

Tong J.,Research Imaging Center | Tong J.,Addiction Imaging Research Group | Fitzmaurice P.,ESR Institute of Environmental Science and Research | Furukawa Y.,Juntendo University | And 7 more authors.
Neurobiology of Disease | Year: 2014

Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain.Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n. = 20) and matched controls (n. = 23). Intact protein levels of all markers were, as expected, elevated (+. 28%-1270%, P<. 0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+. 170%-4700%, P<. 0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P<. 0.05), with positive correlations (r. = 0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P= 0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P= 0.046) and malondialdehyde (P= 0.11).Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that "high" drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic "disturbance" had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users. © 2014 Elsevier Inc.

Boileau I.,Addiction Imaging Research Group | Boileau I.,Campbell Family Mental Health Institute | Boileau I.,University of Toronto | Nakajima S.,Multimodal Imaging Group and Geriatric Mental Health Division | And 3 more authors.
European Neuropsychopharmacology | Year: 2015

Chronic drug use has been associated with dopaminergic abnormalities, detectable in humans with positron emission tomography (PET). Among these, a hallmark feature is low D2 dopamine receptor availability, which has been linked to clinical outcomes, but has not yet translated into a therapeutic strategy. The D3 dopamine receptor on the other hand has gained increasing attention, as, in contrast to D2, chronic exposure to drugs has been shown to up-regulate this receptor subtype in preclinical models of addiction-a phenomenon linked to dopamine system sensitization and drug-seeking. The present article summarizes the literature to date in humans, suggesting that the D3 receptor may indeed contribute to core features of addiction such as impulsiveness and cognitive impairment. A particularly useful tool in investigating this question is the PET imaging probe [11C]-(+)-PHNO, which binds to D2/3 dopamine receptors but has preferential affinity for D3. This technique has been used to demonstrate D3 up-regulation in humans, and can be applied to assess pharmacological interventions for development of D3-targeted strategies in addiction treatment. © 2015 Elsevier B.V. and ECNP.

PubMed | University of Toronto, U.S. National Institute on Drug Abuse, Campbell Family Mental Health Research Institute and Addiction Imaging Research Group
Type: Journal Article | Journal: Biological psychiatry | Year: 2016

One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown.Brain FAAH binding was measured with positron emission tomography and [In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohens d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness.Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

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