Stephen J. Kish

Centre for Addiction and Mental Health, Toronto, Ontario, Canada

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Publications (292)1757.14 Total impact

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    ABSTRACT: For the past 60 years a major theory of “aging” is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defence mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23 to 99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for “replication” investigations employing the new 1H MRS imaging procedures in living human brain.
    No preview · Article · Feb 2016 · Free Radical Biology and Medicine
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    ABSTRACT: Objective: To investigate whether levodopa-induced dyskinesias (LID) are associated with D3 overexpression in levodopa-treated humans with Parkinson disease (PD). Methods: In this case-control study, we used PET with the D3-preferring radioligand [(11)C]-(+)-PHNO to estimate D2/3 receptor binding in patients with levodopa-treated PD with LID (n = 12) and without LID (n = 12), and healthy control subjects matched for age, sex, education, and mental status (n = 18). Results: Compared to nondyskinetic patients, those with LID showed heightened [(11)C]-(+)-PHNO binding in the D3-rich globus pallidus. Both PD groups also showed higher binding than controls in the sensorimotor division of the striatum. In contrast, D2/3 binding in the ventral striatum was lower in patients with LID than without, possibly reflecting higher dopamine levels. Conclusions: Dopaminergic abnormalities contributing to LID may include elevated D2/3 binding in globus pallidus, perhaps reflecting D3 receptor upregulation. The findings support therapeutic strategies that target and diminish activity at D3 to prevent LID.
    No preview · Article · Dec 2015 · Neurology
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    ABSTRACT: We previously reported very low levels of dopamine in postmortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to living brain, we tested whether striatal [¹¹C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [¹¹C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [¹¹C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [¹¹C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support postmortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.Neuropsychopharmacology accepted article preview online, 31 August 2015. doi:10.1038/npp.2015.267.
    No preview · Article · Aug 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    ABSTRACT: Personality disorder symptomatology (PD-Sx) can result in personal distress and impaired interpersonal functioning, even in the absence of a clinical diagnosis, and is frequently comorbid with psychiatric disorders such as substance use, mood, and anxiety disorders; however, they often remain untreated, and are not taken into account in clinical studies. To investigate brain morphological correlates of PD-Sx, we measured subcortical volume and shape, and cortical thickness/surface area, based on structural magnetic resonance images. We investigated 37 subjects who reported PD-Sx exceeding DSM-IV Axis-II screening thresholds, and 35 age, sex, and smoking status-matched control subjects. Subjects reporting PD-Sx were then grouped into symptom-based clusters: N = 20 into Cluster B (reporting Antisocial, Borderline, Histrionic, or Narcissistic PD-Sx) and N = 28 into Cluster C (reporting Obsessive–Compulsive, Avoidant, or Dependent PD-Sx); N = 11 subjects reported PD-Sx from both clusters, and none reported Cluster A (Paranoid, Schizoid, or Schizotypal) PD-Sx. Compared to control, Cluster C PD-Sx was associated with greater striatal surface area localized to the caudate tail, smaller ventral striatum volumes, and greater cortical thickness in right prefrontal cortex. Both Cluster B and C PD-Sx groups also showed trends toward greater posterior caudate volumes and orbitofrontal surface area anomalies, but these findings did not survive correction for multiple comparisons. The results point to morphological abnormalities that could contribute to Cluster C PD-Sx. In addition, the observations parallel those in substance use disorders, pointing to the importance of considering PD-Sx when interpreting findings in often-comorbid psychiatric disorders.
    Full-text · Article · Aug 2015 · Frontiers in Human Neuroscience
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    ABSTRACT: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200mg) compared to lower-dose moclobemide [300-600mg; F(7,16) = 3.94, p = 0.01]. These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets. © The Author 2015. Published by Oxford University Press on behalf of the American Association for Public Opinion Research.
    Full-text · Article · Aug 2015 · The International Journal of Neuropsychopharmacology
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    Full-text · Dataset · Jul 2015
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    ABSTRACT: Cardiovascular and hypothalamic pituitary axis (HPA) disturbances have been observed in individuals who are pathological gamblers (PGs). These may partly derive from chronic exposure to gambling. Response to amphetamine (AMPH) may reveal such disturbances while controlling for differential conditioned responses to gambling in PGs vs healthy controls (HCs). This study assessed heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) and plasma cortisol following oral AMPH (0.4 mg/kg) in male PGs (n=12) and HCs (n=11) who underwent a positron emission tomography (PET) scan. The Stop Signal Task enabled assessment of the link between physiological and behavioral dysregulation. Trait moderating effects were explored. The responses of PGs to AMPH differed from those of HCs on every index. PGs displayed persistent elevation in DBP and concomitant reduction in HR (i.e. baroreflex) compared to HCs beyond 90 min post-dose. PGs displayed deficits in cortisol compared to HCs that were partially reversed by AMPH. Impairment on the Stop Signal Task correlated positively with HR in controls, but negatively with HR in PGs, suggesting that strong initial and compensatory cardiac responses to a stimulant may each predict disinhibition. Extraversion predicted greater disinhibition in PGs. Noradrenergic disturbances may contribute to sensitized responses to stimulant challenge and disinhibition in PGs. © The Author(s) 2015.
    Full-text · Article · Jul 2015 · Journal of Psychopharmacology
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    ABSTRACT: Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen > substantia nigra > caudate > frontal cortex) and PSP (substantia nigra > caudate > putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Neurobiology of Disease
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    ABSTRACT: Positron emission tomography with [(11)C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [(11)C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [(11)C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [(11)C]CURB injection. Oral administration of PF-04457845 reduced [(11)C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test-retest variability=9%; intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[(11)C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 June 2015; doi:10.1038/jcbfm.2015.133.
    Full-text · Article · Jun 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    ABSTRACT: The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [(11)C]CURB ([(11)C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [(11)C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [(11)C]CURB binding (λk3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [(11)C]CURB measurement.Journal of Cerebral Blood Flow & Metabolism advance online publication, 3 June 2015; doi:10.1038/jcbfm.2015.119.
    No preview · Article · Jun 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    ABSTRACT: Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [(11) C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [(11) C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [(11) C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [(11) C]-(+)-PHNO binding is associated with D2 receptor levels, [(11) C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.
    No preview · Article · Jan 2015 · Movement Disorders
  • Yoshiaki Furukawa · Stephen J Kish

    No preview · Article · Jan 2015 · Brain

  • No preview · Article · Jan 2015 · Drug and Alcohol Dependence
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    ABSTRACT: (11)C-carbonyl-URB694 ((11)C-CURB) is a novel (11)C-labeled suicide irreversible radiotracer for PET developed as a surrogate measure of activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase. The aim of the study was to investigate the whole-body biodistribution and estimate the radiation dosimetry from (11)C-CURB scans in humans. Six healthy volunteers (3 men and 3 women) completed a single whole-body scan (∼120 min, 9 time frames) on a PET/CT scanner after administration of (11)C-CURB (∼350 MBq and ∼2 μg). Time-radioactivity curves were extracted in 11 manually delineated organs and corrected for injected activity, specific organ density, and volume to obtain normalized cumulated activities. OLINDA/EXM 1.1 was used to estimate standard internal dose exposure in each organ. The mean effective dose was calculated using the male and female models for the full sample and female-only sample, respectively. (11)C-CURB was well tolerated in all subjects, with no radiotracer-related adverse event reported. The mean effective dose (±SD) was estimated to be 4.6 ± 0.3 μSv/MBq for all subjects and 5.2 ± 0.3 μSv/MBq for the female sample. Organs with the highest normalized cumulated activities (in h) were the liver (0.117), gallbladder wall (0.046), and small intestine (0.033), and organs with the highest dose exposure (in μGy/MBq) were the gallbladder wall (111 ± 60), liver (21 ± 7), kidney (14 ± 3), and small intestine (12 ± 2). Organ radiation exposure for the irreversible fatty acid amide hydrolase enzyme probe (11)C-CURB is within the same range as other radiotracers labeled with (11)C, thus allowing for safe, serial PET scans in the same individuals. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Preview · Article · Nov 2014 · Journal of Nuclear Medicine
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    ABSTRACT: 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.
    No preview · Article · Jul 2014 · Neurobiology of Disease
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    ABSTRACT: Importance Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause.Objective To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years).Design, Setting, and Participants In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11–labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years).Main Outcomes and Measures Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain.Results On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008).Conclusions and Relevance To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.
    Full-text · Article · Jun 2014 · JAMA Psychiatry

  • No preview · Article · Apr 2014 · Journal of clinical psychopharmacology

  • No preview · Article · Jan 2014 · JAMA Psychiatry
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    ABSTRACT: 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 D3 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 D3 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 D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.163.
    Full-text · Article · Dec 2013 · Molecular Psychiatry
  • S.J. Kish
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    ABSTRACT: The objective of this review is to evaluate the evidence that methamphetamine use causes a characteristic brain pathology in human users of the drug for psychoactive purposes.Information on brain pathology is important from a public health point of view and might also provide clues as to new targets for therapeutic intervention in the methamphetamine user.The scope of the review is largely focused on questions whether methamphetamine, as suggested by experimental animal data, might change or damage brain neurons that use dopamine as a neurotransmitter and also cause changes in brain suggestive of neurotoxicity (oxidative stress, gliosis, decreased brain size).The many confounds in human methamphetamine studies make conclusions on brain pathology difficult. There are many generic difficulties and confounds associated with studies of human methamphetamine users designed to establish whether the drug causes harm to the brain. These include lack of proof (e.g. by hair or repeated urine testing) in most investigations that drug users primarily or exclusively used methamphetamine and did not use other drugs that could cause brain pathology, and uncertainty whether changes present in brain were caused by methamphetamine or were a preexisting abnormality. Scatterplots of individual data are also not always provided making it impossible to establish whether brain differences in individual studies are robust.In addition, there is a continuing uncertainty whether differences in levels of any of the brain biochemical markers of dopamine or other neurons possibly affected, can be equated with actual changes in neuronal integrity. In this regard, readers are cautioned to be skeptical of any conclusion in the methamphetamine literature that a change in a brain biochemical neuronal marker necessarily equals loss of part or all of a dopamine neuron.To date, no brain pathology of chronic methamphetamine users has been reported that is a characteristic defining, or obligatory feature. Differences in a variety of brain markers in methamphetamine users have been described, but none can absolutely differentiate methamphetamine users from normal subjects, with levels of most markers showing overlap when comparing ranges of control and drug-user values.Methamphetamine probably causes changes in levels of brain markers of dopamine neurons of some drug users, but it is not clear whether this represents neuronal loss or an otherwise pathological state. A variety of dopamine neuronal markers have been measured in postmortem and/or living brain of methamphetamine users, including dopamine, its metabolites homovanillic acid and dihydroxyphenylacetic acid, the dopamine biosynthetic enzymes tyrosine hydroxylase and dopa decarboxylase, the dopamine and vesicular monoamine (VMAT2) transporters, and several dopamine receptors. Three potentially meaningful findings have been reported:. The first finding, still awaiting replication, is low striatal (caudate, putamen, nucleus accumbens) concentrations of dopamine in autopsied brain of methamphetamine users, all who had recently used the drug. The magnitude of the reduction was near total in some subjects, with little overlap between control and drug user values in caudate, and suggests that high dose methamphetamine, a dopamine releaser, can cause massive release of the neurotransmitter such that tissue stores of dopamine are depleted. Low dopamine might explain some negative aspects of the methamphetamine abstinence syndrome.A second dopamine-related finding is a reduction, typically of modest magnitude, of the striatal dopamine transporter, a change that probably normalizes to some extent in extended abstinence. The transporter difference is the most replicated finding in studies of dopamine markers in methamphetamine users. It has been reported in two postmortem brain investigations and in six independent imaging studies of living brain. It continues to be debated whether low transporter levels (reputedly lasting up to many years of abstinence in some investigations) has functional significance or is associated with loss of transporter-containing dopamine nerve endings.The third observation is the lack, at present, of any marked reduction in striatal levels of some other dopamine neuronal markers, including dopamine metabolites, dopa decarboxylase, and VMAT2, as occurs in Parkinson's disease.Other dopaminerigic changes reported in brain imaging studies include slightly decreased striatal binding to the dopamine D2 receptor, and a preliminary finding of increased binding to the dopamine D3 receptor-differences that might relate to aspects of addiction to methamphetamine, although this link is not yet established.Changes in nondopaminergic markers. These differences include a reduction in biochemical markers of serotonin neurons (generally consistent with animal findings) and decreased striatal concentration of the neuropeptide met-enkephalin-findings consistent with either loss of serotonin and met-enkephalin-containing neurons, or neuroadaptation without neuronal loss.Does methamphetamine cause brain oxidative stress? Animal data suggest that methamphetamine might cause oxidative brain damage, with dopamine-rich brain areas showing higher oxidative stress. Results of a postmortem brain study of methamphetamine users, awaiting replication, support this possibility, with a finding of markedly elevated concentrations of two lipoperoxidation products, 4-hydroxynonenal and malondialdehyde. Changes were most marked in the dopamine-rich striatum and related to drug dose.Studies of brain gliosis of methamphetamine users: Findings are intriguing but no clear picture yet emerges. Microglial activation and reactive astrogliosis are common features of neurotoxic insult. Information on brain gliosis is primarily limited to two methamphetamine investigations: a postmortem investigation in drug users (who had very recently used methamphetamine) reporting increased number of microglial cells in striatum but no increase in activated microgliosis, and a brain imaging study, employing a putative marker of activated microglial cells, showing high binding to the marker throughout the brain of methamphetamine users, withdrawn for up to 2. years after a last drug use. The two gliosis findings are still too preliminary, difficult to reconcile, and (the imaging study) uncertain because of the first generation radiolabelled probe employed, but the question remains whether methamphetamine might induce a progressive, persistent brain neurodegeneration accompanied by gliosis in some subjects.Is methamphetamine exposure associated with smaller or larger brain size? Structural imaging investigations generally suggest slightly lower cerebral cortical gray matter density and striatal enlargement (related to gliosis?) in some drug users. However, the findings are not yet definitive or, in the case of the striatal difference, consistent, and the influence of abstinence time and use of other recreational drugs on the outcome measures remains to be resolved.Increased risk of Parkinson's disease in methamphetamine users? A large longitudinal population-based cohort investigation employing inpatient hospital databases from California reports increased risk of subsequent development of Parkinson's disease in methamphetamine users. This is a preliminary finding, requiring replication, and is associated with many confounds; however, the study does suggest that high dose use of methamphetamine might increase risk of developing Parkinson's disease in later life.Major Conclusions. There is as yet no characteristic or defining brain pathology of chronic methamphetamine users, with the exception of the still undiscovered pathology responsible for compulsive drug taking in the subgroup of chronic methamphetamine users who are addicted to the drug.Regarding brain dopamine-related changes, the reported differences that most impress this reviewer are the striatal dopamine depletion associated with acute drug use, because of the striking magnitude of the change and minimal overlap between drug user and control values, and the striatal dopamine transporter reduction, because of the many replications of the finding in the postmortem brain and brain imaging literature. A severe striatal dopamine transporter reduction (below control levels) is unlikely to be a feature of all methamphetamine users, but future studies of representative numbers of drug users are likely to continue to find a modest mean group reduction in comparison with control values. The lack, to date, of any substantial reduction in other dopamine markers (dopamine metabolites, VMAT2) suggests that if there is any loss of dopamine nerve terminals in methamphetamine users, the extent of loss is probably only typically slight.At present, a statement that methamphetamine causes physical-structural (vs adaptive-neurochemical) damage to dopamine neurons in the human is not justified.In terms of measures that might be related to physical damage to brain neurons, the postmortem brain finding of increased levels of oxidative stress indices is noteworthy because of the large magnitude of the change and association with extent of dopaminergic innervation and drug dose. The glial and structural brain changes in methamphetamine users are both highly provocative but still early, not yet definitive findings, with more work needing to be done to confirm the extent to which these changes occur and are related specifically to methamphetamine use. Glial changes assumed to occur from brain imaging studies must be confirmed by histopathological analysis in postmortem brain. A statement that methamphetamine causes "holes in the brain" is at present unjustified.Recommendations: Regarding the question of methamphetamine as a neurotoxin, my review of the litera
    No preview · Article · Dec 2013

Publication Stats

15k Citations
1,757.14 Total Impact Points


  • 1998-2015
    • Centre for Addiction and Mental Health
      • • Research Imaging Centre
      • • Addictions Research Group
      Toronto, Ontario, Canada
    • University of Campinas
      Conceição de Campinas, São Paulo, Brazil
  • 1983-2015
    • University of Toronto
      • • Department of Psychiatry
      • • Department of Pharmacology and Toxicology
      • • Faculty of Medicine
      • • Institute of Medical Sciences
      Toronto, Ontario, Canada
  • 2014
    • Creatis Medical Imaging Research Center
      Lyons, Rhône-Alpes, France
  • 2007-2008
    • University of Utah
      • Department of Pharmacology and Toxicology
      Salt Lake City, Utah, United States
  • 2002
    • University of Virginia
      • Department of Neurology
      Charlottesville, VA, United States
  • 1999
    • University of Maryland, Baltimore
      • Department of Pathology
      Baltimore, Maryland, United States
  • 1996
    • Emory University
      • Department of Neurology
      Atlanta, Georgia, United States
  • 1993
    • McMaster University
      Hamilton, Ontario, Canada
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1990
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
    • The University of Western Ontario
      London, Ontario, Canada
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1987-1989
    • McGill University
      Montréal, Quebec, Canada
  • 1979-1985
    • University of British Columbia - Vancouver
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      • • Faculty of Pharmaceutical Sciences
      Vancouver, British Columbia, Canada