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Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users

Molecular Psychiatry volume 20, pages 764–771 (2015)Cite this article

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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 [18F]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.

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References

  1. Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 1996; 2: 699–703.

    Article  CAS  Google Scholar 

  2. Hotchkiss AJ, Morgan ME, Gibb JW . The long-term effects of multiple doses of methamphetamine on neostriatal tryptophan hydroxylase, tyrosine hydroxylase, choline acetyltransferase and glutamate decarboxylase activities. Life Sci 1979; 25: 1373–1378.

    Article  CAS  Google Scholar 

  3. Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 2001; 158: 377–382.

    Article  CAS  Google Scholar 

  4. Lee B, London ED, Poldrack RA, Farahi J, Nacca A, Monterosso JR et al. Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity. J Neurosci 2009; 29: 14734–14740.

    Article  CAS  Google Scholar 

  5. Groman SM, Lee B, Seu E, James AS, Feiler K, Mandelkern MA et al. Dysregulation of D(2)-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure. J Neurosci 2012; 32: 5843–5852.

    Article  CAS  Google Scholar 

  6. Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M et al. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 2001; 158: 2015–2021.

    Article  CAS  Google Scholar 

  7. Wang GJ, Smith L, Volkow ND, Telang F, Logan J, Tomasi D et al. Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry 2012; 17: 918–925.

    Article  CAS  Google Scholar 

  8. Morales AM, Lee B, Hellemann G, O'Neill J, London ED . Gray-matter volume in methamphetamine dependence: cigarette smoking and changes with abstinence from methamphetamine. Drug Alcohol Depend 2012; 125: 230–238.

    Article  CAS  Google Scholar 

  9. Schwartz DL, Mitchell AD, Lahna DL, Luber HS, Huckans MS, Mitchell SH et al. Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals. NeuroImage 2010; 50: 1392–1401.

    Article  Google Scholar 

  10. Thompson PM, Hayashi KM, Simon SL, Geaga JA, Hong MS, Sui Y et al. Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 2004; 24: 6028–6036.

    Article  CAS  Google Scholar 

  11. Orikabe L, Yamasue H, Inoue H, Takayanagi Y, Mozue Y, Sudo Y et al. Reduced amygdala and hippocampal volumes in patients with methamphetamine psychosis. Schizophr Res 2011; 132: 183–189.

    Article  Google Scholar 

  12. Groman SM, Morales AM, Lee B, London ED, Jentsch JD . Methamphetamine-induced increases in putamen gray matter associate with inhibitory control. Psychopharmacology (Berl) 2013; 229: 527–538.

    Article  CAS  Google Scholar 

  13. Zorick T, Nestor L, Miotto K, Sugar C, Hellemann G, Scanlon G et al. Withdrawal symptoms in abstinent methamphetamine-dependent subjects. Addiction 2010; 105: 1809–1818.

    Article  Google Scholar 

  14. Ares-Santos S, Granado N, Moratalla R . The role of dopamine receptors in the neurotoxicity of methamphetamine. J Intern Med 2013; 273: 437–453.

    Article  CAS  Google Scholar 

  15. Bozzi Y, Borrelli E . Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it? Trends Neurosci 2006; 29: 167–174.

    Article  CAS  Google Scholar 

  16. Riddle EL, Fleckenstein AE, Hanson GR . Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPS J 2006; 8: E413–E418.

    Article  Google Scholar 

  17. Yamamoto BK, Bankson MG . Amphetamine neurotoxicity: cause and consequence of oxidative stress. Crit Rev Neurobiol 2005; 17: 87–117.

    Article  CAS  Google Scholar 

  18. Cyr M, Beaulieu JM, Laakso A, Sotnikova TD, Yao WD, Bohn LM et al. Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons. Proc Natl Acad Sci USA 2003; 100: 11035–11040.

    Article  CAS  Google Scholar 

  19. Xu W, Zhu JP, Angulo JA . Induction of striatal pre- and postsynaptic damage by methamphetamine requires the dopamine receptors. Synapse 2005; 58: 110–121.

    Article  CAS  Google Scholar 

  20. Khan ZU, Mrzljak L, Gutierrez A, de la Calle A, Goldman-Rakic PS . Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci USA 1998; 95: 7731–7736.

    Article  CAS  Google Scholar 

  21. Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari MS et al. Dopaminergic network differences in human impulsivity. Science 2010; 329: 532.

    Article  CAS  Google Scholar 

  22. Wolf ME, Roth RH . Autoreceptor regulation of dopamine synthesis. Ann NY Acad Sci 1990; 604: 323–343.

    Article  CAS  Google Scholar 

  23. Wong DF, Kuwabara H, Schretlen DJ, Bonson KR, Zhou Y, Nandi A et al. Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving. Neuropsychopharmacology 2006; 31: 2716–2727.

    Article  CAS  Google Scholar 

  24. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci 2006; 26: 6583–6588.

    Article  CAS  Google Scholar 

  25. Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD et al. Acute effects of cocaine on human brain activity and emotion. Neuron 1997; 19: 591–611.

    Article  CAS  Google Scholar 

  26. Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP . Limbic activation during cue-induced cocaine craving. Am J Psychiatry 1999; 156: 11–18.

    Article  CAS  Google Scholar 

  27. Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ et al. Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 2000; 157: 1789–1798.

    Article  CAS  Google Scholar 

  28. Maas LC, Lukas SE, Kaufman MJ, Weiss RD, Daniels SL, Rogers VW et al. Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am J Psychiatry 1998; 155: 124–126.

    Article  CAS  Google Scholar 

  29. Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B, Gatley SJ et al. Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. Am J Psychiatry 1999; 156: 19–26.

    Article  CAS  Google Scholar 

  30. Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 1996; 93: 12040–12045.

    Article  CAS  Google Scholar 

  31. Bonson KR, Grant SJ, Contoreggi CS, Links JM, Metcalfe J, Weyl HL et al. Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 2002; 26: 376–386.

    Article  CAS  Google Scholar 

  32. Hommer DW . Functional imaging of craving. Alcohol Res Health 1999; 23: 187–196.

    CAS  Google Scholar 

  33. Tabibnia G, Monterosso JR, Baicy K, Aron AR, Poldrack RA, Chakrapani S et al. Different forms of self-control share a neurocognitive substrate. J Neurosci 2011; 31: 4805–4810.

    Article  CAS  Google Scholar 

  34. First MB, Spitzer RL, Gibbon M, Williams JB . The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IP). American Psychiatric Press: Washington, DC, 1995.

    Google Scholar 

  35. Ashburner J, Friston KJ . Voxel-based morphometry—the methods. NeuroImage 2000; 11: 805–821.

    Article  CAS  Google Scholar 

  36. Coupe P, Yger P, Barillot C . Fast non local means denoising for 3D MR images. Med Image Comput Comput Assist Interv 2006; 9: 33–40.

    PubMed  Google Scholar 

  37. Rajapakse JC, Giedd JN, Rapoport JL . Statistical approach to segmentation of single-channel cerebral MR images. IEEE Trans Med Imag 1997; 16: 176–186.

    Article  CAS  Google Scholar 

  38. Manjon JV, Tohka J, Garcia-Marti G, Carbonell-Caballero J, Lull JJ, Marti-Bonmati L et al. Robust MRI brain tissue parameter estimation by multistage outlier rejection. Magn Reson Med 2008; 59: 866–873.

    Article  Google Scholar 

  39. Cuadra MB, Cammoun L, Butz T, Cuisenaire O, Thiran JP . Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images. IEEE Trans Med Imag 2005; 24: 1548–1565.

    Article  Google Scholar 

  40. Ashburner J . A fast diffeomorphic image registration algorithm. NeuroImage 2007; 38: 95–113.

    Article  Google Scholar 

  41. Mukherjee J, Yang ZY, Das MK, Brown T . Fluorinated benzamide neuroleptics—III. Development of (S-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer. Nucl Med Biol 1995; 22: 283–296.

    Article  CAS  Google Scholar 

  42. Ardekani BA, Braun M, Hutton BF, Kanno I, Iida H . A fully automatic multimodality image registration algorithm. J Comput Assist Tomogr 1995; 19: 615–623.

    Article  CAS  Google Scholar 

  43. Zald DH, Woodward ND, Cowan RL, Riccardi P, Ansari MS, Baldwin RM et al. The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: a principal component analysis of [18F]fallypride binding. NeuroImage 2010; 51: 53–62.

    Article  CAS  Google Scholar 

  44. Woolrich MW, Jbabdi S, Patenaude B, Chappell M, Makni S, Behrens T et al. Bayesian analysis of neuroimaging data in FSL. NeuroImage 2009; 45: S173–S186.

    Article  Google Scholar 

  45. Lammertsma AA, Hume SP . Simplified reference tissue model for PET receptor studies. NeuroImage 1996; 4: 153–158.

    Article  CAS  Google Scholar 

  46. Mukherjee J, Christian BT, Dunigan KA, Shi B, Narayanan TK, Satter M et al. Brain imaging of 18F-fallypride in normal volunteers: blood analysis, distribution, test-retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D-2/D-3 receptors. Synapse 2002; 46: 170–188.

    Article  CAS  Google Scholar 

  47. Wu Y, Carson RE . Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab 2002; 22: 1440–1452.

    Article  Google Scholar 

  48. Bello EP, Mateo Y, Gelman DM, Noain D, Shin JH, Low MJ et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 2011; 14: 1033–1038.

    Article  CAS  Google Scholar 

  49. Anker JJ, Perry JL, Gliddon LA, Carroll ME . Impulsivity predicts the escalation of cocaine self-administration in rats. Pharmacol Biochem Behav 2009; 93: 343–348.

    Article  CAS  Google Scholar 

  50. Tarter RE, Kirisci L, Habeych M, Reynolds M, Vanyukov M . Neurobehavior disinhibition in childhood predisposes boys to substance use disorder by young adulthood: direct and mediated etiologic pathways. Drug Alcohol Depend 2004; 73: 121–132.

    Article  Google Scholar 

  51. Vidal-Infer A, Arenas MC, Daza-Losada M, Aguilar MA, Minarro J, Rodriguez-Arias M . High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine. Pharmacol Biochem Behav 2012; 102: 124–132.

    Article  CAS  Google Scholar 

  52. Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V . High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 2011; 36: 569–579.

    Article  CAS  Google Scholar 

  53. Zald DH, Cowan RL, Riccardi P, Baldwin RM, Ansari MS, Li R et al. Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans. J Neurosci 2008; 28: 14372–14378.

    Article  CAS  Google Scholar 

  54. Calipari ES, Sun H, Eldeeb K, Luessen DJ, Feng X, Howlett AC et al. Amphetamine self-administration attenuates dopamine d2 autoreceptor function. Neuropsychopharmacology 2014; 39: 1833–1842.

    Article  CAS  Google Scholar 

  55. Kohno M, Morales AM, Ghahremani DG, Hellemann G, London ED . Risky decision making, prefrontal cortex, and mesocorticolimbic functional connectivity in methamphetamine dependence. JAMA Psychiatry 2014; 71: 812–820.

    Article  Google Scholar 

  56. Mukherjee J, Yang ZY, Brown T, Lew R, Wernick M, Ouyang X et al. Preliminary assessment of extrastriatal dopamine D-2 receptor binding in the rodent and nonhuman primate brains using the high affinity radioligand, 18F-fallypride. Nucl Med Biol 1999; 26: 519–527.

    Article  CAS  Google Scholar 

  57. Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong J et al. Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study. J Neurosci 2012; 32: 1353–1359.

    Article  CAS  Google Scholar 

  58. Gurevich EV, Joyce JN . Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 1999; 20: 60–80.

    Article  CAS  Google Scholar 

  59. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR et al. Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. NeuroImage 2008; 39: 1266–1273.

    Article  Google Scholar 

  60. McFarland K, Davidge SB, Lapish CC, Kalivas PW . Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 2004; 24: 1551–1560.

    Article  CAS  Google Scholar 

  61. McFarland K, Lapish CC, Kalivas PW . Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 2003; 23: 3531–3537.

    Article  CAS  Google Scholar 

  62. Nakama H, Chang L, Fein G, Shimotsu R, Jiang CS, Ernst T . Methamphetamine users show greater than normal age-related cortical gray matter loss. Addiction 2011; 106: 1474–1483.

    Article  Google Scholar 

  63. Morales AM, Ghahremani DG, Kohno M, Hellemann G, London ED . Cigarette exposure, dependence and craving are related to insula thickness in young adult smokers. Neuropharmacology 2014; 39: 1816–1822.

    CAS  Google Scholar 

  64. Wrase J, Makris N, Braus DF, Mann K, Smolka MN, Kennedy DN et al. Amygdala volume associated with alcohol abuse relapse and craving. Am J Psychiatry 2008; 165: 1179–1184.

    Article  Google Scholar 

  65. Koob GF, Volkow ND . Neurocircuitry of addiction. Neuropsychopharmacology 2010; 35: 217–238.

    Article  Google Scholar 

  66. Salo R, Ursu S, Buonocore MH, Leamon MH, Carter C . Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study. Biol Psychiatry 2009; 65: 706–709.

    Article  CAS  Google Scholar 

  67. Nestor LJ, Ghahremani DG, Monterosso J, London ED . Prefrontal hypoactivation during cognitive control in early abstinent methamphetamine-dependent subjects. Psychiatry Res 2011; 194: 287–295.

    Article  CAS  Google Scholar 

  68. Drummond DC . Theories of drug craving, ancient and modern. Addiction 2001; 96: 33–46.

    Article  CAS  Google Scholar 

  69. Cadet JL, Krasnova IN . Molecular bases of methamphetamine-induced neurodegeneration. Int Rev Neurobiol 2009; 88: 101–119.

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by NIH Grants P20 DA022539, R01 DA015179, R01 DA020726 (EDL) and M01RR00865 (UCLA GCRC). Additional funding was provided by an endowment from the Thomas P and Katherine K Pike Chair in Addiction Studies and a gift from the Marjorie M Greene Trust. Drs Morales and Kohno were supported by F31 DA033117 and F31 DA033120, respectively, as well as T32 DA024635. None of the sponsors were involved with the design, collection, analysis or interpretation of data, writing the manuscript or the decision to submit the manuscript for publications.

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Authors and Affiliations

  1. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA

    A M Morales, M Kohno, C L Robertson, A C Dean & E D London

  2. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA

    C L Robertson & E D London

  3. Departments of Brain Research Institute, University of California, Los Angeles, CA, USA

    A C Dean & E D London

  4. Department of Physics, University of California Irvine, Irvine, CA, USA

    M A Mandelkern

  5. Veterans Administration of Greater Los Angeles Health System, Los Angeles, CA, USA

    M A Mandelkern & E D London

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Morales, A., Kohno, M., Robertson, C. et al. Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users. Mol Psychiatry 20, 764–771 (2015). https://doi.org/10.1038/mp.2015.47

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