title: Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release.
abstract: Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [(11)C]cocaine to measure DAT, and with [(11)C]raclopride to measure dopamine release (assessed as changes in specific binding of [(11)C]raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.
authors.affiliation: Laboratory of Neuroimaging, Intramural Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA; Office of Director, National Institute on Drug Abuse, Bethesda, MD, USA. Electronic address: nvolkow@nida.nih.gov.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.affiliation: Laboratory of Neuroimaging, Intramural Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of California, Los Angeles, CA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smith
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: Laboratory of Neuroimaging, Intramural Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Telang
authors.affiliation: Laboratory of Neuroimaging, Intramural Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.affiliation: Laboratory of Neuroimaging, Intramural Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Dardo
authors.initials: D
authors.lastname: Tomasi
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000000981:diagnostic imaging / Q000378:metabolism*; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism*; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011699:Putamen / Q000000981:diagnostic imaging / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
chemical_list: C581293:DRD2 protein, human; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D008694:Methamphetamine
keywords: Addiction; Dopamine terminal; Neurotoxicity; Parkinson's disease