title: Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.
abstract: Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Morales
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kohno
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA [2] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA [2] Departments of Brain Research Institute, University of California, Los Angeles, CA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Dean
authors.affiliation: 1] Department of Physics, University of California Irvine, Irvine, CA, USA [2] Veterans Administration of Greater Los Angeles Health System, Los Angeles, CA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Mandelkern
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA [2] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA [3] Departments of Brain Research Institute, University of California, Los Angeles, CA, USA [4] Veterans Administration of Greater Los Angeles Health System, Los Angeles, CA, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: London
mesh_terms: D001549:Benzamides / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D058999:Drug-Seeking Behavior / Q000502:physiology*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D066128:Gray Matter / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D008694:Methamphetamine / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012044:Regression Analysis; D019966:Substance-Related Disorders / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D019788:Fluorodeoxyglucose F18; D008694:Methamphetamine; C574003:fallypride