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Deficits in Dopamine D2 Receptors and Presynaptic Dopamine in Heroin Dependence: Commonalities and Differences with Other Types of Addiction

      Background

      Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D2/3 receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior.

      Methods

      Heroin-dependent and healthy control subjects were scanned with [11C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D2/3 receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions.

      Results

      Both striatal D2/3 receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin.

      Conclusions

      These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D2/3 receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin.

      Key Words

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      References

        • Martinez D.
        • Kim J.H.
        • Krystal J.
        • Abi-Dargham A.
        Imaging the neurochemistry of alcohol and substance abuse.
        Neuroimaging Clin N Am. 2007; 17 (x): 539-555
        • Volkow N.D.
        • Fowler J.S.
        • Wang G.J.
        • Baler R.
        • Telang F.
        Imaging dopamine's role in drug abuse and addiction.
        Neuropharmacology. 2009; 56: 3-9
        • Breier A.
        • Su T.P.
        • Saunders R.
        • Carson R.E.
        • Kolachana B.S.
        • deBartolomeis A.
        • et al.
        Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method.
        Proc Natl Acad Sci U S A. 1997; 94: 2569-2574
        • Laruelle M.
        Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review.
        J Cereb Blood Flow Metab. 2000; 20: 423-451
        • Volkow N.D.
        • Wang G.-J.
        • Fowler J.S.
        • Logan J.
        • Schlyer D.
        • Hitzemann R.
        • et al.
        Imaging endogenous dopamine competition with [11C]raclopride in the human brain.
        Synapse. 1994; 16: 255-262
        • Hietala J.
        • West C.
        • Syvalahti E.
        • Nagren K.
        • Lehikoinen P.
        • Sonninen P.
        • et al.
        Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence.
        Psychopharmacology. 1994; 116: 285-290
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.S.
        • Logan J.
        • Hitzemann R.
        • Ding Y.S.
        • et al.
        Decreases in dopamine receptors but not in dopamine transporters in alcoholics.
        Alcohol Clin Exp Res. 1996; 20: 1594-1598
        • Wang G.J.
        • Volkow N.D.
        • Fowler J.S.
        • Logan J.
        • Abumrad N.N.
        • Hitzemann R.J.
        • et al.
        Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal.
        Neuropsychopharmacology. 1997; 16: 174-182
        • Volkow N.D.
        • Chang L.
        • Wang G.J.
        • Fowler J.S.
        • Ding Y.S.
        • 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
        • Volkow N.D.
        • Fowler J.S.
        • Wang G.J.
        • Hitzemann R.
        • Logan J.
        • Schlyer D.J.
        • et al.
        Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.
        Synapse. 1993; 14: 169-177
        • Martinez D.
        • Broft A.
        • Foltin R.W.
        • Slifstein M.
        • Hwang D.R.
        • Huang Y.
        • et al.
        Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: Relationship with cocaine-seeking behavior.
        Neuropsychopharmacology. 2004; 29: 1190-1202
        • Lee B.
        • London E.D.
        • Poldrack R.A.
        • Farahi J.
        • Nacca A.
        • Monterosso J.R.
        • et al.
        Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity.
        J Neurosci. 2009; 29: 14734-14740
        • Zijlstra F.
        • Booij J.
        • van den Brink W.
        • Franken I.H.
        Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males.
        Eur Neuropsychopharmacol. 2008; 18: 262-270
        • Fehr C.
        • Yakushev I.
        • Hohmann N.
        • Buchholz H.G.
        • Landvogt C.
        • Deckers H.
        • et al.
        Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse.
        Am J Psychiatry. 2008; 165: 507-514
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.S.
        • Logan J.
        • Gatley S.J.
        • Hitzemann R.
        • et al.
        Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.
        Nature. 1997; 386: 830-833
        • Martinez D.
        • Gil R.
        • Slifstein M.
        • Hwang D.R.
        • Huang Y.
        • Perez A.
        • et al.
        Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.
        Biol Psychiatry. 2005; 58: 779-786
        • Martinez D.
        • Narendran R.
        • Foltin R.W.
        • Slifstein M.
        • Hwang D.R.
        • Broft A.
        • et al.
        Amphetamine-induced dopamine release: Markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine.
        Am J Psychiatry. 2007; 164: 622-629
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.S.
        • Logan J.
        • Gatley S.J.
        • Gifford A.
        • et al.
        Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.
        Am J Psychiatry. 1999; 156: 1440-1443
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.S.
        • Thanos P.
        • Logan J.
        • Gatley S.J.
        • et al.
        Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study.
        Synapse. 2002; 46: 79-82
        • Thanos P.K.
        • Volkow N.D.
        • Freimuth P.
        • Umegaki H.
        • Ikari H.
        • Roth G.
        • et al.
        Overexpression of dopamine D2 receptors reduces alcohol self-administration.
        J Neurochem. 2001; 78: 1094-1103
        • Thanos P.K.
        • Michaelides M.
        • Umegaki H.
        • Volkow N.D.
        D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats.
        Synapse. 2008; 62: 481-486
        • Morgan D.
        • Grant K.A.
        • Gage H.D.
        • Mach R.H.
        • Kaplan J.R.
        • Prioleau O.
        • et al.
        Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration.
        Nat Neurosci. 2002; 5: 169-174
        • Wang R.I.
        • Wiesen R.L.
        • Lamid S.
        • Roh B.L.
        Rating the presence and severity of opiate dependence.
        Clin Pharmacol Ther. 1974; 16: 653-658
        • Volkow N.D.
        • Wang G.
        • Fowler J.S.
        • Logan J.
        • Gerasimov M.
        • Maynard L.
        • et al.
        Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.
        J Neurosci. 2001; 21: RC121
      1. Martinez D, Carpenter KM, Liu F, Slifstein M, Broft A, Friedman AC, et al. Imaging dopamine transmission in cocaine dependence: Link between neurochemistry and response to treatment. Am J Psychiatry 168:634–641.

        • Lammertsma A.A.
        • Hume S.P.
        Simplified reference tissue model for PET receptor studies.
        Neuroimage. 1996; 4: 153-158
        • Innis R.B.
        • Cunningham V.J.
        • Delforge J.
        • Fujita M.
        • Gjedde A.
        • Gunn R.N.
        • et al.
        Consensus nomenclature for in vivo imaging of reversibly binding radioligands.
        J Cereb Blood Flow Metab. 2007; 27: 1533-1539
        • Slifstein M.
        • Laruelle M.
        Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers.
        Nucl Med Biol. 2001; 28: 595-608
        • Mawlawi O.
        • Martinez D.
        • Slifstein M.
        • Broft A.
        • Chatterjee R.
        • Hwang D.R.
        • et al.
        Imaging human mesolimbic dopamine transmission with PET: I.
        J Cereb Blood Flow Metab. 2001; 21: 1034-1057
        • Martinez D.
        • Slifstein M.
        • Broft A.
        • Mawlawi O.
        • Hwang D.R.
        • Huang Y.
        • et al.
        Imaging human mesolimbic dopamine transmission with positron emission tomography.
        J Cereb Blood Flow Metab. 2003; 23: 285-300
        • Comer S.D.
        • Sullivan M.A.
        • Whittington R.A.
        • Vosburg S.K.
        • Kowalczyk W.J.
        Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers.
        Neuropsychopharmacology. 2008; 33: 1179-1191
        • Comer S.D.
        • Collins E.D.
        • MacArthur R.B.
        • Fischman M.W.
        Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans.
        Psychopharmacology. 1999; 143: 327-338
        • Georges F.
        • Stinus L.
        • Bloch B.
        • Le Moine C.
        Chronic morphine exposure and spontaneous withdrawal are associated with modifications of dopamine receptor and neuropeptide gene expression in the rat striatum.
        Eur J Neurosci. 1999; 11: 481-490
        • Sanchez-Cardoso P.
        • Higuera-Matas A.
        • Martin S.
        • Miguens M.
        • Del Olmo N.
        • Garcia-Lecumberri C.
        • et al.
        Strain differences between Lewis and Fischer 344 rats in the modulation of dopaminergic receptors after morphine self-administration and during extinction.
        Neuropharmacology. 2009; 57: 8-17
        • Melis M.
        • Spiga S.
        • Diana M.
        The dopamine hypothesis of drug addiction: Hypodopaminergic state.
        Int Rev Neurobiol. 2005; 63: 101-154
        • Diana M.
        • Pistis M.
        • Muntoni A.
        • Gessa G.
        Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats.
        J Pharmacol Exp Ther. 1995; 272: 781-785
        • Diana M.
        • Muntoni A.L.
        • Pistis M.
        • Melis M.
        • Gessa G.L.
        Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal.
        Eur J Neurosci. 1999; 11: 1037-1041
        • Spiga S.
        • Serra G.P.
        • Puddu M.C.
        • Foddai M.
        • Diana M.
        Morphine withdrawal-induced abnormalities in the VTA: Confocal laser scanning microscopy.
        Eur J Neurosci. 2003; 17: 605-612
        • Bonci A.
        • Williams J.T.
        Increased probability of GABA release during withdrawal from morphine.
        J Neurosci. 1997; 17: 796-803
        • Madhavan A.
        • Bonci A.
        • Whistler J.L.
        Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area.
        J Neurosci. 2010; 30: 14029-14035
        • Manzoni O.J.
        • Williams J.T.
        Presynaptic regulation of glutamate release in the ventral tegmental area during morphine withdrawal.
        J Neurosci. 1999; 19: 6629-6636
        • Di Chiara G.
        • Bassareo V.
        Reward system and addiction: What dopamine does and doesn't do.
        Curr Opin Pharmacol. 2007; 7: 69-76
        • Comer S.D.
        • Collins E.D.
        • Fischman M.W.
        Choice between money and intranasal heroin in morphine-maintained humans.
        Behav Pharmacol. 1997; 8: 677-690
      2. Skinbjerg M, Liow JS, Seneca N, Hong J, Lu S, Thorsell A, et al. D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: A PET study in a receptor internalization-deficient mouse model. Neuroimage 50:1402–1407.