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Sacher J.,Vivian koff Pet Imaging Center | Sacher J.,University of Toronto | Sacher J.,Max Planck Institute for Human Cognitive and Brain Sciences | Houle S.,Vivian koff Pet Imaging Center | And 7 more authors.
Journal of Psychiatry and Neuroscience | Year: 2011

Background: Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties. Methods: Participants underwent 2 [ 11C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A V T, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. Results: We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A V T decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F 1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A V T. Limitations: The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%. Conclusion: For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade dring moclobemide treatment exceeds the elevation of MAO-A binding during illness by at least 30%, suggesting that the treatment effect should exceed the disease effect when designing selective anti-depressants for this target. © 2011 Canadian Medical Association. Source


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. Source


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 26 more authors.
Addiction | Year: 2013

Aims: Pathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. Design: Case-control study comparing PG to healthy control (HC) subjects. Setting: Academic research imaging centre. Participants: Thirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). Measurements: Two PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. Findings: Binding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P>0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r=0.57, P=0.04) and impulsiveness (r=0.65, P=0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r=-0.70, P=0.03) and impulsiveness (r=-0.70, P=0.03). Conclusions: Unlike with substance use disorder, there appear to be no marked differences in D2/D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction. Source

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