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Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428
Open accessAbstract
Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [11C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for approximately 3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (-23 and -24%, respectively) and putamen (-25 and -16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
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“Alternatively, studies in methamphetamine abusers show a consistent and long lasting decrease in the dopamine transporter, which is the main target of this drug (Chou et al., 2007; Johanson et al., 2006; McCann et al., 1998; McCann et al., 2008; Sekine et al., 2001; Volkow et al., 2001b).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as McCann et al., 1998
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Cites
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“…years abstaining from METH use, positron emission tomography scans revealed a loss of dopamine transporters among former METH users (Wilson et al. 1996; McCann et al. 1998; Volkow et al. 2001a,b), and magnetic resonance imaging studies suggest that METH also induced cell death (Ernst et al. 2000).”
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BackgroundInsights from recent positron emission tomographic studies of drug abuse and dependence
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“The neurotoxic effects of methamphetamine appear to have significant clinical implications, as neurological deficits have been found in human clinical populations of chronic methamphetamine abusers (McCann et al. 1998; Schep et al. 2010; Volkow et al. 2001a, b ; Wilson et al. 1996).”
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“Chronic administration of methamphetamine reduces the levels of dopamine transporters in the striatum, orbitofrontal and dorsolateral prefrontal cortex, and amygdala (McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001; Sekine et al., 2003).”
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“McCann and colleagues found a reduction in DAT density in the caudate (23% less) and the putamen (25% less) of MA abusers compared to control subjects (McCann et al. 1998).”
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Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals
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“This paradigm of Meth exposure is comparable to that used by human Meth users (McCann et al. 1998) and produces deficits in DA transmission (Volkow et al. 2001; Callaghan et al. 2012).”
MethodLaćan, G., Hadamitzky, M., Kuczenski, R. T., & Melega, W. P. (2013) · Synapse · doi:10.1002/syn.21654 · Cited by 20
“…striatal dopamine system integrity have been identified by positron emission tomography (PET) imaging during METH abstinence (Johanson et al., 2006; McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001) but assessment of further alterations occurring acutely during time periods when METH…”
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“Physiological dependence on METH has variable associations with craving and other symptoms of drug use (Newton et al., 2009).”
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Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction
Hou, H., Tian, M., & Zhang, H. (2012) · The Anatomical Record · doi:10.1002/ar.22457 · Cited by 20
“[11C] CFT has been used to find the reduction of DAT in methamphetamine abusers and in baboons after methamphetamine injection (McCann et al., 1998; Villemagne et al., 1998; Sekine et al., 2001; Sekine et al., 2003).”
MethodGraham, D. L., Amos‐Kroohs, R. M., Braun, A. A., Grace, C. E., Schaefer, T. L., Skelton, M. R., Williams, M. T., & Vorhees, C. V. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712000144 · Cited by 19
“…preclinical data have shown that adult Meth exposure can induce long-lasting decreases in levels of the DA transporter (Fleckenstein et al. 1997; Johanson et al. 2006; Kokoshka et al. 1998; McCann et al. 1998; Sekine et al. 2001; Volkow et al. 2001b; Wilson et al. 1996), Int J Neuropsychopharmacol.”
BackgroundMorgan, E. E., Woods, S. P., Poquette, A., Vigil, O., Heaton, R. K., & Grant, I. (2012) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867411433212 · Cited by 19
“, 2007) revealed a slightly larger effect size for learning as compared to delayed recall across studies, which was hypothesized to reflect deficient executive control of encoding and retrieval secondary to MA-related toxicity in the prefronto−striatal pathways (McCann et al., 1998; Volkow et al., 2001a).”
BackgroundNorman, L. R., & Basso, M. R. (2015) · Current Drug Abuse Reviews · doi:10.2174/1874473708666150309124820 · Cited by 19
Bowyer, J. F., Tranter, K. M., Sarkar, S., George, N. I., Hanig, J. P., Kelly, K. A., Michalovicz, L. T., Miller, D. B., & O'Callaghan, J. P. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14143 · Cited by 18
“A number of published reports document the ability of METH and AMPH to cause neurotoxicity in humans (Rothrock et al. 1988; Wilson et al. 1996; McCann et al. 1998; Ernst et al. 2000; Volkow et al. 2001a,b; McCann and Received March 23, 2017; revised manuscript received August 1, 2017; accepted…”
BackgroundLin, J. C., Jan, R. K., Kydd, R., & Russell, B. (2015) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2015.01.026 · Cited by 20
Neuroreceptor Imaging in Psychiatry: Theory and Applications
Frankle, W. G., Slifstein, M., Talbot, P. S., & Laruelle, M. A. (2005) · International review of neurobiology · doi:10.1016/s0074-7742(05)67011-0 · Cited by 19
Gutierrez, A., Williams, M. T., & Vorhees, C. V. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9871-9 · Cited by 18
“…dopamine (DA) and serotonin (5-HT) transporters (DAT and SERT, respectively) in the caudate-putamen by positron emission tomography and postmortem reductions in striatal DA levels (Chang et al. 2007; Kish et al. 2009; McCann et al. 1998; Sekine et al. 2006; Volkow et al. 2001; Wilson et al. 1996).”
Verbal learning impairment in adolescents with methamphetamine use disorder: a cross-sectional study
Basedow, L. A., Kuitunen‐Paul, S., Wiedmann, M. F., Ehrlich, S., Roessner, V., & Golub, Y. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03169-3 · Cited by 18
Herbal Marijuana Alternatives and Bath Salts—“Barely Legal” Toxic Highs
Lindsay, L., & White, M. L. (2012) · Clinical Pediatric Emergency Medicine · doi:10.1016/j.cpem.2012.09.001 · Cited by 18
Perseverative behavior in rats with methamphetamine-induced neurotoxicity
Son, J., Kuhn, J., & Keefe, K. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.09.021 · Cited by 19
“The long-term consequences of METH abuse include a partial, but persistent, loss of dopamine (DA) and serotonin (5-HT) systems in multiple brain areas, such as striatum, cortex, and hippocampus (Kish et al., 2009; McCann et al., 1998; Morgan and Gibb, 1980; Ricaurte et al., 1980; Seiden et al., 1976; Volkow et al., 20…”
BackgroundBaladi, M. G., Newman, A. H., Nielsen, S. M., Hanson, G. R., & Fleckenstein, A. E. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.03.023 · Cited by 18
“Methamphetamine use can produce both acute and long-term changes in dopaminergic neurons, as demonstrated in rodents (Hadlock et al., 2010; Metzger et al., 2000), non-human primates (Melega et al., 1997), and humans (McCann et al., 1998; Wilson et al., 1996).”
BackgroundMethamphetamine self‐administration acutely decreases monoaminergic transporter function
McFadden, L. M., Stout, K. A., Vieira‐Brock, P. L., Allen, S. C., Nielsen, S. M., Wilkins, D. G., Hanson, G. R., & Fleckenstein, A. E. (2011) · Synapse · doi:10.1002/syn.21506 · Cited by 18
“Chronic METH abuse is associated with neurochemical, psychiatric, and cognitive impairments that persist long after the short-term effects of the drug have been subsided (McCann et al., 1998, 2008; Sekine et al., 2001; Volkow et al., 2001).”
Wang, J., Xu, W., Ali, S. F., & Angulo, J. A. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1432.001 · Cited by 18
Monoaminergic dysfunction in recreational users of dexamphetamine
Schouw, M. L. J., Caan, M. W. A., Geurts, H. M., Schmand, B. A., Booij, J., Nederveen, A. J., & Reneman, L. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.01.005 · Cited by 18
Hayley, A. C., Shiferaw, B. A., & Downey, L. A. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101929 · Cited by 18
Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson’s Disease?
Baumeister, A. A. (2021) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000283 · Cited by 17
“DAT levels begin to recover after a year of abstinence(267) but remain decreased for up to three years.(265) Fi-”
BackgroundSiedlecka-Kroplewska, K., Szczerba, A., Lipińska, A. D., Ślebioda, T. J., & Kmieć, Z. (2014) · PubMed · Cited by 17
Effects of Housing on Methamphetamine-Induced Neurotoxicity and Spatial Learning and Memory
Gutierrez, A., Jablonski, S. A., Amos‐Kroohs, R. M., Barnes, A. C., Williams, M. T., & Vorhees, C. V. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00419 · Cited by 17
Blaker, A. L., Rodriguez, E. A., & Yamamoto, B. K. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.06.028 · Cited by 18
Tulloch, I., Afanador, L., Mexhitaj, I., Ghazaryan, N. A., GarzaGongora, A. G., & Angulo, J. A. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.07.020 · Cited by 17
“For example, studies utilizing positron emission tomography showed decreased levels of dopamine transporter (McCann et al., 1998; Sekine et al., 2001) and serotonin transporter sites (Sekine et al., 2006) in various brain regions including the caudate and putamen.”
BackgroundDevelopment of Parkinson’s disease in patients with Narcolepsy
Christine, C. W., Marks, W. J., & Ostrem, J. L. (2012) · Journal of Neural Transmission · doi:10.1007/s00702-011-0761-z · Cited by 17
Serial exposure to ethanol drinking and methamphetamine enhances glutamate excitotoxicity
Blaker, A. L., Moore, E. R., & Yamamoto, B. K. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14861 · Cited by 18
Biomarkers of adult and developmental neurotoxicity
Slikker, W., & Bowyer, J. F. (2005) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2004.09.022 · Cited by 17
Alhassoon, O. M., Dupont, R. M., Schweinsburg, B. C., Taylor, M. J., Patterson, T. L., & Grant, I. (2001) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145701002334 · Cited by 17
Kosheleff, A. R., Grimes, M., O’Dell, S. J., Marshall, J. F., & Izquierdo, A. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2367-4 · Cited by 16
“…human users’ binge style of consumption and, if administered at sufficiently high doses, result in brain monoamine-depleting effects similar to those observed in the human mAMPH-abusing population (Wilson et al. 1996; McCann et al. 1998; Sekine et al. 2001; Volkow et al. 2001; Kish et al. 2009).”
ResultIn vivo imaging of neurotransmitter systems in neuropsychiatry
Wong, D. F., & Brašić, J. R. (2001) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(00)00005-0 · Cited by 17
Pereira, F. C., Imam, S. Z., Gough, B., Newport, G. D., Ribeiro, C., SLIKKER, W., Macedo, T. R. A., & Ali, S. F. (2002) · Journal of Neural Transmission · doi:10.1007/s00702-002-0754-z · Cited by 16
“Wilson et al. (1996) and McCann et al. (1998) reported that METH induced DA transporter reduction in human brain, which suggests that METH at the doses abused by humans also affects the dopamine terminals (Cadet and Brannock, 1998).”
BackgroundDrugs of Abuse in HIV infection and neurotoxicity
Hidalgo, M., Atluri, V. S. R., & Nair, M. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00217 · Cited by 16
Substance Abuse and Movement Disorders
Luciano, M. S., & Saunders-Pullman, R. J. (2009) · Current Drug Abuse Reviews · doi:10.2174/1874473710902030273 · Cited by 16
“DAT sites in abstinent users of these substances in a similar fashion as in Parkinson’s disease, possibly indicating permanent damage of striatal dopamine axon and axon terminals [47].”
ResultTraumatic brain injury and methamphetamine: A double-hit neurological insult
Hayek, S. E., Allouch, F., Razafsha, M., Talih, F. R., Gold, M. S., Wang, K., & Kobeissy, F. H. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116711 · Cited by 18
GOMES‐DA‐SILVA, J., Pérez‐Rosado, A., de Miguel, R., Fernández‐Ruíz, J., da Silva, C. A. L., & Tavares, M. A. (2002) · PubMed · Cited by 16
Impact of COMT Val158Met on executive functioning in the context of HIV and methamphetamine
Bousman, C. (2010) · Neurobehavioral HIV Medicine · doi:10.2147/nbhiv.s8245 · Cited by 16
“long been established as a dopaminergic agonist that results in synaptic dopamine influxes acutely and intracellular dopamine deficits over long-term exposure; 11,12 whereas, HIV-infection has been shown to lower dopamine levels in the cerebrospinal fluid 13–15 and postmortem human brains.”
Lindsey, K. P., Gatley, S. J., & Volkow, N. D. (2003) · Current Psychiatry Reports · doi:10.1007/s11920-003-0068-3 · Cited by 15
“and in humans [5].”
The Effect of Co-occurring Substance Use on Gamma-hydroxybutyric Acid Withdrawal Syndrome
Kamal, R. M., Dijkstra, B. A. G., LOONEN, A. J. M., & de Jong, C. A. J. (2016) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000214 · Cited by 16
“The chronic use of psychostimulants depletes monoamine neurotransmitter stores such as those of serotonin and NE, and it has been suggested that this may be associated with decreases in dopamine transporters (Volkow et al., 1997; McCann et al., 1998; Volkow et al., 2001).”
BackgroundBowyer, J. F. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02925-5 · Cited by 16
Central Nervous System Alterations in Drug Abuse
Büttner, A., & Weis, S. (2004) · Forensic pathology reviews · doi:10.1007/978-1-59259-786-4_4 · Cited by 16
Effects of Prenatal Exposure to Methamphetamine on the Development of the Rat Retina
de Melo, P. L., Rodrigues, L. G., da Silva, C. A. L., & Ferreira, M. A. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1369.058 · Cited by 16
Yang, S., Belcher, A. M., Chefer, S. I., Vaupel, D. B., Schindler, C. W., Stein, E. A., & Yang, Y. (2013) · Addiction Biology · doi:10.1111/adb.12078 · Cited by 15
“Data from human METH users recapitulate these pre-clinical findings of monoamine terminal loss (Wilson et al. 1996; McCann et al. 1998; Volkow et al. 2001b; Sekine et al. 2006) and have been extended to include structural abnormalities in the striatum (Chang et al.”
Clinical neuroscience of amphetamine-type stimulants
Courtney, K. E., & Ray, L. A. (2015) · Progress in brain research · doi:10.1016/bs.pbr.2015.07.010 · Cited by 15
“…(Groman et al., 2012; Volkow et al., 2001a), VMAT-2 density ( Johanson et al., 2006), SERT density (Sekine et al., 2006), and DAT site density (McCann et al., 1998; Villemagne et al., 1998; Volkow et al., 2001b,c), with some markers (i.e., DAT density) showing improvement following prolonged…”
BackgroundMolecular Imaging of Biological Processes with PET: Evaluating Biologic Bases of Cerebral Function
Silverman, D. H. S., & Melega, W. P. (2004) · Springer eBooks · doi:10.1007/978-0-387-22529-6_7 · Cited by 15
Vuorenpää, A., Jørgensen, T. N., Newman, A. H., Madsen, K. L., Scheinin, M., & Gether, U. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.702050 · Cited by 15
“For example, differential up- and down-regulation of brain NET and DAT, respectively, was reported upon chronic cocaine or methamphetamine exposure in humans (47, 78).”
Background
Metadata
- Authors
- McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., & Ricaurte, G. A.
- Affiliations
- National Institute of Mental Health (US)
- Johns Hopkins University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-10-15
- Volume
- 18
- Issue
- 20
- Pages
- 8417-8422
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6792853
- OpenAlex
- W2106287416
- Cited by
- 602
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 19 · 2020: 11 · 2019: 12 · 2018: 14 · 2017: 16 · 2016: 16 · 2015: 27 · 2014: 32 · 2013: 38 · 2012: 34
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da009482-05, 5r01da006275-03)
- National Institute of Mental Health
- National Institute on Drug Abuse (F32DA005707, DA05707, DA09482, DA-06275, R01DA005707)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- methamphetamine, methcathinone, amphetamine abuse, dopamine transporter density, striatum, caudate nucleus, putamen, dopamine neuron loss, Parkinson's disease, psychostimulants, neurotoxicity
- MeSH terms
- Adult, Central Nervous System Stimulants, Brain Chemistry, Carbon Radioisotopes, Carrier Proteins, Cocaine, Female, Humans, Male, Membrane Glycoproteins, Methamphetamine, Middle Aged, Nerve Tissue Proteins, Parkinson Disease, Secondary, Propiophenones, Tomography, Emission-Computed, Neostriatum, Dopamine Uptake Inhibitors, Amphetamine-Related Disorders, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins
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