title: Heightened Dopaminergic Response to Amphetamine at the D3Dopamine Receptor in Methamphetamine Users.
abstract: Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D2/3receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3receptor levels in stimulant users prompting the view that D3antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [11C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [11C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [11C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3dopamine receptor may contribute to motivation to use drugs and argues in favor of D3antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Addictions Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boileau
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Addictions Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Doris
authors.identifier: 0000-0001-9313-2587
authors.initials: D
authors.lastname: Payer
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Rusjan
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: McCluskey
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Addictions Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000328:Adult; D000661:Amphetamine / Q000009:adverse effects / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D000704:Analysis of Variance; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D018491:Dopamine Agonists / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D010078:Oxazines; D050637:Receptors, Dopamine D3; C042631:naxagolide; D000661:Amphetamine