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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
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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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“Positron emission tomography (PET) has demonstrated that compared with corresponding measures in control subjects, MA abusers exhibit lower levels of dopamine transporters in the striatum (McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001) and prefrontal cortex (Sekine et al.”
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“…of investigators have also tested the possibility that MDMA can cause degenerative effects in the human brain (Ricaurte et al., 1988a; 1990; Price et al., 1989; McCann et al., 1994; 1998a; 1999; Bolla et al., 1998; Semple et al., 1999; Gerra et al., 2000; Kish et al., 2000; Buchert et al., 2001).”
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“…oes it appear to be related to PD or drug use disorders; and (5) rior epidemiological studies have successfully used individuals ith appendicitis-related conditions as a basis for hospital-based opulation-proxy control groups (Mueller et al., 1990; Lin et al., 008a,b; Callaghan and Khizar, 2010).”
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Jernigan, T. L., Gamst, A. C., Archibald, S. L., Fennema‐Notestine, C., Mindt, M. R., Marcotte, T. D., Heaton, R. K., Ellis, R. J., & Grant, I. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.8.1461 · Cited by 268
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“This is problematic, because it is well established that high-dose administration of these stimulants can cause long-lasting monoaminergic deficits in humans (McCann et al., 1998; Reneman et al., 2001; Sekine et al., 2001) and nonhuman models (Hotchkiss et al.”
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“DAT binding sites in former MA abusers is consistent with previous PET studies of abstinent MA abusers ( McCann et al. 1998; Volkow et al. 2001b).”
BackgroundResultInfluentialGender differences in methamphetamine use and responses: A review
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“Other reports of neurotoxic effects of METH in human abusers indicate poor motor performance associated with DAT loss in the caudate nucleus and putamen (Volkow et al., 2001a,b; McCann et al., 1998).”
BackgroundPerfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users
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Methamphetamine Abstinence Syndrome: Preliminary Findings
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“Consistent with these observations, neuroimaging studies also found significantly lower DAT binding in the brains of methamphetamine users [124, 196].”
Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users
McCann, U. D., Kuwabara, H., Kumar, A., Palermo, M., Abbey, R., Brašić, J. R., Ye, W., Alexander, M., Dannals, R. F., Wong, D. F., et al. (2007) · Synapse · doi:10.1002/syn.20471 · Cited by 205
“A growing body of data suggests that METH-induced DA/ 5-HT neurotoxicity generalizes to humans (Johanson et al., 2006; McCann et al., 1998; Sekine et al., 2001, 2003, 2006; Volkow et al., 2001a,b; Wilson et al., 1996a).”
BackgroundMethodResultInfluentialDeng, X., Wang, Y., Chou, J., & Cadet, J. L. (2001) · Molecular Brain Research · doi:10.1016/s0169-328x(01)00184-x · Cited by 200
Impaired time perception and motor timing in stimulant-dependent subjects
Wittmann, M., Leland, D. S., Churan, J., & Paulus, M. P. (2007) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2007.03.005 · Cited by 210
“it leads to downregulation of striatal D2 dopamine receptors (Chang and Haning, 2006) and dopamine transporters in the striatum (McCann et al., 1998), orbitofrontal cortex, and dorsolateral prefrontal cortex (Sekine et al.”
BackgroundInfluentialGerman, C. L., Baladi, M. G., McFadden, L. M., Hanson, G. R., & Fleckenstein, A. E. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.010397 · Cited by 207
“, 2007), and these decreases persist for years after abstinence (McCann et al., 1998).”
BackgroundNeurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine
Halpin, L. E., Collins, S. A., & Yamamoto, B. K. (2013) · Life Sciences · doi:10.1016/j.lfs.2013.07.014 · Cited by 199
“…and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005) Neurochemical markers of this toxicity include decreases in the expression of…”
BackgroundMicroglial activation is a pharmacologically specific marker for the neurotoxic amphetamines
Thomas, D. M., Dowgiert, J., Geddes, T. J., Francescutti, D. M., Liu, X., & Kuhn, D. M. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.06.065 · Cited by 192
Frascella, J., Potenza, M. N., Brown, L. L., & Childress, A. R. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05420.x · Cited by 203
Vearrier, D., Greenberg, M. I., Miller, S. N., Okaneku, J., & Haggerty, D. A. (2012) · Disease-a-Month · doi:10.1016/j.disamonth.2011.09.004 · Cited by 191
Causes and consequences of methamphetamine and MDMA toxicity
Quinton, M. S., & Yamamoto, B. K. (2006) · The AAPS Journal · doi:10.1007/bf02854904 · Cited by 188
Substance Abuse Among Adolescents
Sussman, S. Y., Skara, S. N., & Ames, S. L. (2008) · Substance Use & Misuse · doi:10.1080/10826080802297302 · Cited by 188
“, the striatum) for as long as 3 years following cessation of use (McCann et al., 1998).”
BackgroundChronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging
London, E. D., Kohno, M., Morales, A. M., & Ballard, M. E. (2014) · Brain Research · doi:10.1016/j.brainres.2014.10.044 · Cited by 192
“…generally lower in abstinent methamphetamine users than in matched non-users: deficits of 11-28% were measured using [11C]WIN-35,428 and [11C]d-threomethylphenidate (Johanson et al., 2006; McCann et al., 1998; McCann et al., 2008; Sekine et al., 2001; Volkow et al., 2001b; Volkow et al., 2001d).”
MethodFlupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence
Soyka, M., & Vry, J. D. (2000) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(00)00088-2 · Cited by 187
Smith, L. M., YONEKURA, M. L., Tm, W., Berman, N., KUO, J., & Berkowitz, C. D. (2003) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/00004703-200302000-00006 · Cited by 182
“Two positron emission tomography studies in abstinent methamphetamine abusers demonstrated decreased dopamine transporters, which indicates long-lasting neurotoxicity as a result of methamphetamine abuse.(37,38) Thus, the relatively low rate of severe withdrawal symptoms noted does not indicate protection of the devel…”
BackgroundThe confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview
Gouzoulis‐Mayfrank, E., & Daumann, J. (2006) · Journal of Psychopharmacology · doi:10.1177/0269881106059939 · Cited by 179
Neurotoxic methamphetamine regimen severely impairs recognition memory in rats
Schröder, N., O’Dell, S. J., & Marshall, J. F. (2003) · Synapse · doi:10.1002/syn.10210 · Cited by 179
“Similar damage can occur in humans who self-administer these compounds (Wilson et al., 1996; McCann et al., 1998; Volkow et al., 2001a,b).”
BackgroundAdditive Effects of HIV and Chronic Methamphetamine Use on Brain Metabolite Abnormalities
Chang, L., Ernst, T. M., Speck, O., & Grob, C. S. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.2.361 · Cited by 178
“tem study (8) and positron emission tomography (PET) studies (9, 10) consistently found lower concentrations of”
BackgroundDopamine transporter imaging with [123I]FP-CIT SPECT: potential effects of drugs
Booij, J., & Kemp, P. M. (2007) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-007-0621-0 · Cited by 175
Kohno, M., Morales, A. M., Ghahremani, D. G., Hellemann, G., & London, E. D. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.399 · Cited by 179
Neurochemical Targets and Behavioral Effects of Organohalogen Compounds: An Update
Mariussen, E., & Fonnum, F. (2006) · Critical Reviews in Toxicology · doi:10.1080/10408440500534164 · Cited by 175
“Other environmental factors suggested to be involved in the development of Parkinson’s disease are drugs acting on the monoaminergic system (McCann et al., 1998; Sandoval et al., 2003), or other pesticides, which interfere with the electron transport, such as rotenone and carbamates, and infectious…”
BackgroundCurrent Research on Methamphetamine-Induced Neurotoxicity: Animal Models of Monoamine Disruption
Kita, T., Wagner, G. C., & Nakashima, T. (2003) · Journal of Pharmacological Sciences · doi:10.1254/jphs.92.178 · Cited by 173
Kish, S. J., Lerch, J. P., Furukawa, Y., Tong, J., McCluskey, T., Wilkins, D. G., Houle, S., Meyer, J. H., Mundo, E., Wilson, A. A., et al. (2010) · Brain · doi:10.1093/brain/awq103 · Cited by 172
“…(even within the same laboratory) with respect to presence, magnitude and regional extent of brain areas affected [e.g. massive global brain (McCann et al., 1998a) versus regionally selective reduction (McCann et al., 2005, 2008); striatal involvement (caudate, putamen; Buchert et al.,…”
BackgroundInfluentialImaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity
Trifilieff, P., & Martinez, D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.031 · Cited by 171
“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, 2008; Sekine et al., 2001; Volkow et al., 2001b).”
BackgroundThe Neuropsychology of Amphetamine and Opiate Dependence: Implications for Treatment
Ersche, K. D., & Sahakian, B. J. (2007) · Neuropsychology Review · doi:10.1007/s11065-007-9033-y · Cited by 175
“Although the neurotoxicity of amphetamines in humans is still a matter of debate, druginduced changes in the dopamine system may be dosedependent (Sung et al. 2007) and be long-lasting (Johanson et al. 2006; McCann et al. 1998; Sekine et al. 2001; Volkow et al. 2001b).”
BackgroundYamamoto, B. K., & Raudensky, J. (2008) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-008-9121-7 · Cited by 167
“Clinical studies using functional magnetic resonance imaging to measure changes in DAT levels in human METH abusers indicate that chronic use of METH results in decreased DAT in the striatum that persists for up to 3 years following abstinence (McCann et al. 1998).”
BackgroundDopamine transport function is elevated in cocaine users
Mash, D. C., Pablo, J. P., Ouyang, Q., Hearn, W. L., & Izenwasser, S. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00820.x · Cited by 168
Patterns of Methamphetamine Abuse and Their Consequences
Cho, A. K., & Melega, W. P. (2001) · Journal of Addictive Diseases · doi:10.1300/j069v21n01_03 · Cited by 166
Jayanthi, S., Deng, X., BORDELON, M., McCoy, M. T., & Cadet, J. L. (2001) · The FASEB Journal · doi:10.1096/fj.01-0025com · Cited by 165
Bupropion Reduces Methamphetamine-Induced Subjective Effects and Cue-Induced Craving
Newton, T. F., Roache, J. D., Garza, R. D. L., FONG, T. W., Wallace, C. L., Li, S.-H., Elkashef, A. M., Chiang, N., & Kahn, R. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300979 · Cited by 163
“These symptoms may be due to methamphetamineinduced neuroadaptations in presynaptic DA neurons manifest as reduced striatal DA availability (McCann et al, 1998; Sekine et al, 2003; Volkow et al, 2001; Wilson et al, Online publication: 20 October 2005 at http://www.acnp.org/citations/…”
BackgroundGluck, M. R., Moy, L. Y., Jayatilleke, E., Hogan, K. A., Manzino, L., & Sonsalla, P. K. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00549.x · Cited by 153
Ares‐Santos, S., Granado, N., Espadas, I., Martínez‐Murillo, R., & Moratalla, R. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.307 · Cited by 151
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148
“Additionally, abstinent MDMA users perform worse on tests of memory function, and their performance on these tests is correlated with insular and hippocampal SERT binding (McCann et al., 1998a, 2008; Kish et al., 2010).”
BackgroundNeurocognitive Impairment and HIV Risk Factors: A Reciprocal Relationship
Anand, P., Springer, S. A., Copenhaver, M. M., & Altice, F. L. (2010) · AIDS and Behavior · doi:10.1007/s10461-010-9684-1 · Cited by 149
“In human methamphetamine users, loss of dopamine axonal proteins consistent with injury to axon terminals of dopaminergic neurons has been observed [22, 28].”
BackgroundJones, K. L., & Barr, G. A. (2000) · Synapse · doi:10.1002/1098-2396(200102)39:2 · Cited by 11
Burrows, K. B., Gudelsky, G. A., & Yamamoto, B. K. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00264-8 · Cited by 145
Wu, C.-W., Ping, Y., Yen, J., Chang, C., Wang, S., Yeh, C.-L., Chi, C., & Lee, H. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.01.011 · Cited by 143
Amphetamine neurotoxicity: accomplishments and remaining challenges
McCann, U. D., & Ricaurte, G. A. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.11.003 · Cited by 142
The role of dopamine receptors in the neurotoxicity of methamphetamine
Ares‐Santos, S., Granado, N., & Moratalla, R. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12049 · Cited by 138
Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers
London, E. D., Berman, S. M., Voytek, B., Simon, S. L., Mandelkern, M. A., Monterosso, J., Thompson, P. M., Brody, A. L., Geaga, J. A., Hong, M. S., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.04.039 · Cited by 136
“Positron emission tomography (PET) reveals losses of cereral dopamine transporters (McCann et al 1998; Sekine et al 2001, 003; Volkow et al 2001c) and abnormalities of global and egional cerebral glucose metabolism (rCMRglc) in MA abusers London et al 2004; Volkow et al 2001a; Wang et al 2004).…”
BackgroundMoszczyńska, A., & Callan, S. P. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.238501 · Cited by 136
How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy?
Kish, S. J. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00708-0 · Cited by 132
Ladenheim, B., Krasnova, I. N., Deng, X., Oyler, J. M., Polettini, A., Moran, T. H., Huestis, M. A., & Cadet, J. L. (2000) · Molecular Pharmacology · doi:10.1124/mol.58.6.1247 · Cited by 131
Ujike, H., Harano, M., Inada, T., Yamada, M., Komiyama, T., Sekine, Y., Sora, I., Iyo, M., Katsu, T., Nomura, A., et al. (2003) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500189 · Cited by 130
Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure
González, R., Rippeth, J. D., Carey, C. L., Heaton, R. K., Moore, D. J., Schweinsburg, B. C., Cherner, M., & Grant, I. (2004) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2004.04.014 · Cited by 128
“, 2000 ), and decreased density of dopaminergic neurons in the caudate and putamen ( McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001b).”
BackgroundHarvey, D. C., Laćan, G., Tanious, S. P., & Melega, W. P. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02439-2 · Cited by 127
Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects
Newton, T. F., Garza, R. D. L., Kalechstein, A. D., & Nestor, L. J. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.07.012 · Cited by 125
Guilarte, T. R., Nihei, M. K., McGlothan, J. L., & Howard, A. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00476-7 · Cited by 125
“…of dopaminergic and/or serotonergic terminal markers induced by METH can persist for long periods of time in rodents (Friedman et al., 1998; Cass and Manning, 1999; Cass, 2000) non-human primates (Melega et al., 1997; Harvey et al., 2000) and in humans (McCann et al., 1998; Volkow et al., 2001).”
BackgroundPsychiatric Comorbidity of Methamphetamine Dependence in a Forensic Sample
Kalechstein, A. D., Newton, T. F., Longshore, D. L., Anglin, M. D., van Gorp, W. G., & Gawin, F. H. (2000) · Journal of Neuropsychiatry · doi:10.1176/jnp.12.4.480 · Cited by 127
Licata, S. C., & Renshaw, P. F. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05143.x · Cited by 119
Prospective memory impairment in former users of methamphetamine
Rendell, P. G., Mazur, M., & Henry, J. D. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1408-0 · Cited by 120
“For instance, a positron emission tomography study by McCann et al. (1998) found that dopamine receptor density was significantly reduced in abstinent methamphetamine users, even though the drug users had an average length of abstinence of 3 years.”
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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