Abstract
Animal data have long suggested that an adaptive upregulation of nucleus accumbens dopamine D1 receptor function might underlie part of the dependency on drugs of abuse. We measured by quantitative immunoblotting protein levels of dopamine D1 and, for comparison, D2 receptors in brain of chronic users of methamphetamine, cocaine, and heroin. As compared with the controls, brain dopamine D1 receptor concentrations were selectively increased (by 44%) in the nucleus accumbens of the methamphetamine users, whereas a trend was observed in this brain area for reduced protein levels of the dopamine D2 receptor in all three drug groups (−25 to −37%; P < 0.05 for heroin group only). Our data support the hypothesis that aspects of the drug-dependent state in human methamphetamine users might be related to increased dopamine D1 receptor function in limbic brain.
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References
Di Chiara G . The role of dopamine in drug abuse viewed from the perspective of its role in motivation Drug Alcohol Depend 1995; 38: 95–137
Nestler EJ, Aghajanian GK . Molecular and cellular basis of addiction Science 1997; 278: 58–63
Self DW . Neural substrates of drug craving and relapse in drug addiction Ann Med 1998; 30: 379–389
Higashi H, Inanaga K, Nishi S, Uchimura N . Enhancement of dopamine actions on rat nucleus accumbens neurones in vitro after methamphetamine pre-treatment J Physiol 1989; 408: 587–603
Henry DJ, White FJ . Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens J Pharmacol Exp Ther 1991; 258: 882–890
Terwilliger RZ, Beitner-Johnson D, Sevarino E, Crain SM, Nestler EJ . A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function Brain Res 1991; 548: 100–110
Self DW, McClenahan AW, Beitner-Johnson D, Terwilliger RZ, Nestler EJ . Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration Synapse 1995; 21: 312–318
Schoffelmeer AN, Voorn P, Jonkeer AJ, Wardeh G, Nestby P, Vanderschuren LJ et al. Morphine-induced increase in D-1 receptor regulated signal transduction in rat striatal neurons and its facilitation by glucocorticoid receptor activation: possible role in behavioral sensitization Neurochem Res 1996; 21: 1417–1423
Unterwald EM, Fillmore J, Kreek MJ . Chronic repeated cocaine administration increases dopamine D1 receptor-mediated signal transduction Eur J Pharmacol 1996; 318: 31–35
Self DW, Barnhart WJ, Lehman DA, Nestler EJ . Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists Science 1996; 271: 1586–1589
Hall H, Farde L, Sedvall G . Human dopamine receptor subtypes—in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride J Neural Transm 1988; 73: 7–21
Dean B, Pavey G, Opeskin K . [3H]Raclopride binding to brain tissue from subjects with schizophrenia: methodological aspects Neuropharmacology 1997; 36: 779–786
Ng GYK, O'Dowd BF, Lee SP, Chung HT, Brann MR, Seeman P et al. Dopamine D2 receptor dimers and receptor-blocking peptides Biochem Biophys Res Comm 1996; 227: 200–204
Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users Nature Med 1996; 2: 699–703
Wilson JM, Levey AI, Bergeron C, Kalasinsky K, Ang L, Peretti F et al. Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users Ann Neurol 1996; 40: 428–439
Kish SJ, Kalasinsky K, Furukawa Y, Guttman M, Ang L, Adams V et al. Brain choline acetyltransferase activity in chronic human users of cocaine, methamphetamine, and heroin Mol Psychiatry 1999; 4: 26–32
Riley HA . An Atlas of the Basal Ganglia, Brainstem, and Spinal Cord Hafner: New York 1960
Kish SJ, Shannak K, Hornykiewicz O . Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease New Engl J Med 1988; 318: 876–880
McLeman ER, Warsh JJ, Ang L, Li PP, Kalasinsky KS, Ross BM et al. The human nucleus accumbens is highly susceptible to G protein down-regulation by methamphetamine and heroin J Neurochem 2000; 74: 2120–2126
Meredith GE, Pattiselanno A, Groenwegen HJ, Haber SN . Shell and core in monkey and human nucleus accumbens identified with antibodies to calbindin-D28k J Comp Neurol 1996; 365: 628–639
Voorn P, Brady LS, Berendse HW, Richfield EK . Densitometrical analysis of opioid receptor ligand binding in the human striatum—I. Distribution of μ opioid receptor defines shell and core of the ventral striatum Neuroscience 1996; 75: 777–792
Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies Proc Natl Acad Sci (USA) 1993; 90: 8861–8865
Smiley JF, Levey AI, Ciliax BJ, Goldman-Rakic PS . D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex Proc Natl Acad Sci (USA) 1994; 91: 5720–5724
Hersch SM, Ciliax BJ, Gutekunst CA, Rees HD, Heilman CJ, Yung KK et al. Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents J Neurosci 1995; 15: 5222–5237
Maltais S, Labbé L, Falardeau P . Characterization of a polyclonal anti-D2 dopamine receptor antibody to D2R third intracellular loop fusion protein Soc Neurosci USA Abstr 1995; 21: 365
Maltais S, Côté S, Drolet G, Falardeau P . Cellular colocalization of dopamine D1 mRNA and D2 receptor in rat brain using a D2dopamine receptor specific polyclonal antibody Prog Neuro-Psychopharmacol Biol Psychiat 2000; 24: (in press)
Turjanski N, Weeks R, Dolan R, Harding AE, Brooks DJ . Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study Brain 1995; 118: 689–696
Ginovart N, Lundin A, Farde L, Halldin C, Backman L, Swahn CG et al. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease Brain 1997; 120: 503–514
Antonini A, Leenders KL, Eidelberg D . [11C]raclopride-PET studies of the Huntington's disease rate of progression: relevance of the trinucleotide repeat length Ann Neurol 1998; 43: 253–255
Hall H, Sedvall G, Magnusson O, Kopp J, Hallidin C, Farde L . Distribution of D1- and D2- dopamine receptors, and dopamine and its metabolites in the human brain Neuropsychopharmacology 1994; 11: 245–256
Meador-Woodruff JH, Little KY, Damask SP, Mansour A, Watson SJ . Effects of cocaine on dopamine receptor gene expression: a study in the postmortem human brain Biol Psychiatry 1993; 34: 348–355
Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer DJ et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers Synapse 1993; 14: 169–177
Staley JK, Wetli CV, Ruttneber AJ, Heam WL, Mash DC . Altered dopaminergic synaptic markers in cocaine psychosis and sudden death NIDA Res Monogr 1995; 153: 491
Wang G-J, Volkow ND, Fowler JS, Logan J, Abumrad NN, Hitzemann RJ et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal Neuropsychopharmacology 1997; 16: 174–182
Robinson TE, Becker JB . Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis Brain Res 1986; 396: 157–198
Barnett JV, Segal DS, Kuczenski R . Repeated amphetamine pretreatment alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization J Pharmacol Exp Ther 1987; 242: 40–47
Nonaka R, Moroji T . Effects of chronic methamphetamine treatment on the binding parameters of [3H]SCH 23390, a selective D1-dopamine receptor ligand, in the rat brain Neurosci Lett 1990; 120: 109–112
Ujike H, Akiyama K, Nishikawa H, Onoue T, Otsuki S . Lasting increase in D1 dopamine receptors in the lateral part of the substantia nigra pars reticulata after subchronic methamphetamine administration Brain Res 1991; 540: 159–163
Bonhomme N, Cador M, Stinus L, Le Moal M, Spampinato U . Short and long-term changes in dopamine and serotonin receptor binding sites in amphetamine-sensitized rats: a quantitative autoradiographic study Brain Res 1995; 675: 215–223
Susuki H, Shishido T, Watanabe Y, Abe H, Shiragata M, Honda K et al. Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration Prog Neuropsychopharmacol Biol Psychiatry 1997; 21: 359–369
Tomic M, Joksimovic J . Psychotomimetics moderately affect dopamine receptor binding in the rat brain Neurochem Int 2000; 36: 137–142
Tomic M, Slobodanka V, Joksimovic J . Acute amphetamine and/or phencyclidine effects on the dopamine receptor specific binding in the rat brain Eur Neuropsychopharmacol 1997; 7: 295–301
Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR . Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine Eur J Pharmacol 1999; 371: 123–135
McCabe RT, Hanson GR, Dawson TM, Wamsley JK, Gibb JW . Methamphetamine-induced reduction in D1 and D2 dopamine receptors as evidenced by autoradiography: comparison with tyrosine hydroxylase activity Neuroscience 1987; 23: 253–261
Cadet JL, Ladenheim B, Hirata H . Effects of toxic doses of methamphetamine (METH) on dopamine D1 receptors in the mouse brain Brain Res 1998; 786: 240–242
Staley JK, Mash DC . Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities J Neurosci 1996; 16: 6100–6106
Zubieta J-K, Gorelick DA, Stauffer R, Ravert HT, Dannals RF, Frost JJ . Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving Nature Med 1996; 2: 1225–1229
Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC . Kappa2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims J Neurosci 1997; 17: 8225–8233
Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ . Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior J Neurosci 1998; 18: 1848–1859
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This study was supported by US NIH NIDA No. DA 07182 to SJK.
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Worsley, J., Moszczynska, A., Falardeau, P. et al. Dopamine D1 receptor protein is elevated in nucleus accumbens of human, chronic methamphetamine users. Mol Psychiatry 5, 664–672 (2000). https://doi.org/10.1038/sj.mp.4000760
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DOI: https://doi.org/10.1038/sj.mp.4000760
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