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Agonist high- and low-affinity states of dopamine D2 receptors: methods of detection and clinical implications

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Abstract

Dopamine D2 receptors, similar to other G-protein-coupled receptors, exist in a high- and low-affinity state for agonists. Based upon a review of the methods for detecting D2 receptor agonist high-affinity states, we discuss alterations of such states in animal models of disease and the implications of such alterations for their labelling with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. The classic approach of detecting agonist high-affinity states compares agonist competition for antagonist radioligands, in most cases using [3H]-spiperone as the radioligand; alternative approaches and radioligands have been proposed, but their claimed advantages have not been substantiated by other investigators. In view of the advantages and disadvantages of various techniques, we critically have reviewed reported findings on the detection of D2 receptor agonist high-affinity states in a variety of animal models. These data are compared to the less numerous findings from human in vivo studies based on PET and SPECT tracers; they are interpreted in light of the finding that D2 receptor agonist high-affinity states under control conditions may differ between rodent and human brain. The potential advantages of agonist ligands in studies of pathophysiology and as diagnostics are being discussed.

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Abbreviations

COMT:

Catechol-O-methyl transferase

D2high :

Agonist high-affinity state of the D2 dopamine receptor

DBH:

Dopamine β-hydroxylase

GPCR:

G-protein-coupled receptor

Gprk6:

G-protein-coupled receptor kinase 6

MNPA:

2-Methoxy-N-propylnorapomorphine

NMSP:

N-methylspiperone

NPA:

N-propylnorapomorphine

PET:

Positron emission tomography

SPECT:

Single-photon emission computed tomography

DAT:

Dopamine transporter

VMAT:

Vesicular monoamine transporter

References

  • Abolfathi Z, Di Paolo T (1991) Modulation of dopamine receptor agonist binding sites by cations and estradiol in intact pituitary and 7315a tumors. Biochem Pharmacol 42:2163–2169

    Article  PubMed  CAS  Google Scholar 

  • Akunne HC, Towers P, Ellis GJ, Dijkstra D, Wikstrom H, Heffner TG, Wise LD, Pugsley TA (1995) Characterization of binding of [3H]PD 128907, a selective dopamine D3 receptor agonist ligand, to CHO-K1 cells. Life Sci 57:1401–1410

    Article  PubMed  CAS  Google Scholar 

  • Alttoa A, Seeman P, Koiv K, Eller M, Harro J (2009) Rats with persistently high exploratory activity have both higher extracellular dopamine levels and higher proportion of D(2) (High) receptors in the striatum. Synapse 63:443–446

    Article  PubMed  CAS  Google Scholar 

  • Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C, Halbout B, Jacobsen J, Kinoshita C, Welter M, Caron MG, Bonci A, Sulzer D, Borrelli E (2012) Dual control of dopamine synthesis and release by presynaptic and postsynatpic D2 receptors. J Neurosci 32:9023–9034

    Article  PubMed  CAS  Google Scholar 

  • Armstrong D, Strange PG (2001) Dopamine D2 receptor dimer formation—evidence from ligand binding. J Biol Chem 276:22621–22629

    Article  PubMed  CAS  Google Scholar 

  • Auning E, Rongve A, Fladby T, Booij J, Hortobagyi T, Siepel FJ, Ballard C, Aarsland D (2011) Early and presenting symptoms of dementia with lewy bodies. Dement Geriatr Cogn 32:202–208

    Google Scholar 

  • Baudry M, Martres MP, Schwartz JC (1979) [3H]domperidone: a selective ligand for dopamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 308:231–237

    Article  CAS  Google Scholar 

  • Boileau I, Guttman M, Rusjan P, Jr A, Houle S, Tong JC, Hornykiewicz O, Furukawa Y, Wilson AA, Kapur S, Kish SJ (2009) Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naïve Parkinson's disease. Brain 132:1366–1375

    Article  PubMed  Google Scholar 

  • Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong JC, Wilkins D, Selby P, George TP, Zack M, Furukawa Y, Mccluskey T, Wilson AA, Kish SJ (2012) 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 32:1353–1359

    Article  PubMed  CAS  Google Scholar 

  • Booij J, Van Amelsvoort TA (2012) Imaging as tool to investigate psychoses and antipsychotics. Handb Exp Pharmacol 212:299–377

    Article  PubMed  Google Scholar 

  • Booij J, Tissingh G, Winogrodzka A, Van Royen EA (1999) Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism. Eur J Nucl Med 26:171–182

    Article  PubMed  CAS  Google Scholar 

  • Boot E, Booij J, Hasler G, Zinkstok DE Jr, Haan L, Linszen DH, Van Amelsvoort TA (2008) AMPT-induced monoamine depletion in humans: evaluation of two alternative [123i]IBZM SPECT procedures. Eur J Nucl Med Mol Imag 35:1350–1356

    Article  Google Scholar 

  • Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, De Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–2574

    Article  PubMed  CAS  Google Scholar 

  • Briand LA, Flagel SB, Seeman P, Robinson TE (2008) Cocaine self-administration produces a persistent increase in dopamine D2 High receptors. Eur Neuropsychopharmacol 18:551–556

    Article  PubMed  CAS  Google Scholar 

  • Burt DR, Creese I, Snyder SH (1977) Anti-schizophrenic drugs—chronic treatment elevates dopamine receptor-binding in brain. Science 196:327–328

    Article  Google Scholar 

  • Cannon M, Jones PB, Murray RM (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 159:1080–1092

    Article  PubMed  Google Scholar 

  • Creese I, Burt DR, Snyder SH (1977) Dopamine receptor-binding enhancement accompanies lesion-induced behavioral supersensitivity. Science 197:596–598

    Article  PubMed  CAS  Google Scholar 

  • Creese I, Padgett L, Fazzini E, Lopez F (1979) 3H-N-n-propylnorapomorphine: a novel agonist ligand for central dopamine receptors. Eur J Pharmacol 56:411–412

    Article  PubMed  CAS  Google Scholar 

  • Cumming P (2011) Absolute abundances and affinity states of dopamine receptors in mammalian brain: a review. Synapse 65:892–909

    Article  PubMed  CAS  Google Scholar 

  • Cumming P, Wong DF, Dannals RF, Gillings N, Hilton J, Scheffel U, Gjedde A (2002a) The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors. Ann Ny Acad Sci 965:440–450

    Article  PubMed  CAS  Google Scholar 

  • Cumming P, Wong DF, Gillings N, Hilton J, Scheffel U, Gjedde A (2002b) Specific binding of [11C]raclopride and N-[3H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein. J Cerebr Blood Flow Metabol 22:596–604

    Article  CAS  Google Scholar 

  • Curran C, Byrappa N, Mcbride A (2004) Stimulant psychosis: systematic review. Br J Psychiatry 185:196–204

    Article  PubMed  Google Scholar 

  • De Lean A, Bf K, Mg C (1982) Dopamine receptor of the porcine anterior pituitary gland. Evidence for two affinity states discriminated by both agonists and antagonists. Mol Phamacol 22:290–297

    Google Scholar 

  • Di Paolo T, Levesque D (1988) Sodium and guanine nucleotide regulation of dopamine receptor agonist and antagonist binding sites in MtTW15 pituitary tumors. Can J Physiol Pharmacol 66:246–249

    Article  PubMed  Google Scholar 

  • Dumbrille-Ross A, Seeman P (1987) Dopamine agonist high-affinity state in solubilized D2 receptors in striatum, but not in anterior pituitary. Biochem Pharmacol 36:2095–2099

    Article  PubMed  CAS  Google Scholar 

  • El-Ghundi M, O'dowd BF, Sr G (2001) Prolonged fear responses in mice lacking dopamine D1 receptor. Brain Res 892:86–93

    Article  PubMed  CAS  Google Scholar 

  • Elsinga PH, Hatano K, Ishiwata K (2006) Pet tracers for imaging of the dopaminergic system. Curr Med Chem 13:2139–2153

    Article  PubMed  CAS  Google Scholar 

  • Erdbrügger W, Raulf M, Otto T, Michel MC (1995) Does [3H]2-methoxy-idazoxan (RX-821002) detect more alpha-2-adrenoceptor agonist high-affinity sites than [3H]rauwolscine—a comparison of nine tissues and cell-lines. J Pharmacol Exp Ther 273:1287–1294

    PubMed  Google Scholar 

  • Fields JZ, Reisine TD, Yamamura HI (1977) Biochemical demonstration of dopaminergic receptors in rat and human brain using [3H]spiroperidol. Brain Res 136:578–584

    Article  PubMed  CAS  Google Scholar 

  • Findell PR, Torkelson SM, Craig JC, Weiner RI (1988) Correlation of alpha- and beta-rotameric forms of 2-substituted octahydrobenzo[f]quinoline dopamine congeners with high and low affinity states of the anterior pituitary dopamine receptor and prolactin inhibition. Mol Phamacol 33:78–83

    CAS  Google Scholar 

  • Finnema S, Halldin C, Halldin C, Bang-Andersen B, Gulyas B, Bundgaard C, Wikström HV, Farde L (2009a) Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain—a comparative pet study with [11C]raclopride and [11C]MNPA. Synapse 63:378–389

    Article  PubMed  CAS  Google Scholar 

  • Finnema SJ, Halldin C, Bang-Andersen B, Gulyás B, Bundgaard C, Wikström HV, Farde L (2009b) Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain—a comparative pet study with [11C]raclopride and [11C]MNPA. Synapse 63:378–389

    Article  PubMed  CAS  Google Scholar 

  • Finnema SJ, Bang-Andersen B, Wikstrom HV, Halldin C (2010) Current state of agonist radioligands for imaging of brain dopamine D2/D3 receptors in vivo with positron emission tomography. Curr Top Med Chem 10:1477–1498

    Article  PubMed  CAS  Google Scholar 

  • Flagel SB, Robinson TE, Clark JJ, Clinton SM, Watson SJ, Seeman P, Phillips PEM, Akil H (2010) An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction. Neuropsychopharmacology 35:388–400

    Article  PubMed  Google Scholar 

  • Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, Mcallister G (1994) Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther 268:417–426

    PubMed  CAS  Google Scholar 

  • Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT (2003) Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron 38:291–303

    Article  PubMed  CAS  Google Scholar 

  • George S, Watanabe M, Paolo T, Falardeau P, Labrie F, Seeman P (1985) The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form. Endocrinology 117:690–697

    Article  PubMed  CAS  Google Scholar 

  • Ginovart N, Galineau L, Willeit M, Mizrahi R, Pm B, Seeman P, Houle S, Kapur S, Wilson AA (2006) Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography. J Neurochem 97:1089–1103

    Article  PubMed  CAS  Google Scholar 

  • Ginovart N, Wilson AA, Hussey D, Houle S, Kapur S (2009) D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal [11C]-raclopride pet study in cats. Neuropsychopharmacology 34:662–671

    Article  PubMed  CAS  Google Scholar 

  • Graff-Guerrero A, Mizrahi R, Agid O, Marcon H, Barsoum P, Rusjan P, Wilson AA, Zipursky R, Kapur S (2008) The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: a clinical [11C]-(+)-PHNO pet study. Neuropsychopharmacology 34:1078–1086

    Article  PubMed  CAS  Google Scholar 

  • Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, Rusjan P, Houle S, Wilson AA, Kapur S (2009) The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study with [11]C-(+)-PHNO. Arch Gen Psychiatry 66:606–615

    Article  PubMed  CAS  Google Scholar 

  • Grigoriadis D, Seeman P (1986) [3H]-domperidone labels only a single population of receptors which convert from high to low affinity for dopamine in rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 332:21–25

    Article  CAS  Google Scholar 

  • Hall H, Halldin C, Dijkstra D, Wikström H, Wise LD, Pugsley TA, Sokoloff P, Pauli S, Farde L, Sedvall G (1996) Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907. Psychopharmacology 128:240–247

    Article  PubMed  CAS  Google Scholar 

  • Hamblin MW, Creese I (1982) 3H-dopamine binding to rat striatal D-2 and D-3 sites: enhancement by magnesium and inhibition by guanine-nucleotides and sodium. Life Sci 30:1587–1595

    Article  PubMed  CAS  Google Scholar 

  • Hamblin MW, Leff SE, Creese I (1984) Interactions of agonists with D2 dopamine receptors: evidence for a single receptor population existing in multiple agonist affinity-states in rat striatal membranes. Biochem Pharmacol 33:877–887

    Article  PubMed  CAS  Google Scholar 

  • Hein P, Bunemann M (2009) Coupling mode of receptors and G proteins. Naunyn-Schmiedeberg's Arch Pharmacol 379:435–443

    Article  CAS  Google Scholar 

  • Hein P, Michel MC (2005) Radioligand binding studies in cardiovascular research (saturation and competition binding studies). In: Dhein S, Mohr FW, Delmar M (eds) Practical methods in cardiovascular research. Springer, Heidelberg, pp 703–727

    Google Scholar 

  • Hendriks-Balk MC, Peters SLM, Michel MC, Alewijnse AE (2008) Regulation of G protein-coupled receptor signalling: focus on the cardiovascular system and regulator of G protein signalling proteins. Eur J Pharmacol 585:278–291

    Article  PubMed  CAS  Google Scholar 

  • Hirvonen J, Hietala J (2011) Dysfunctional brain networks and genetic risk for schizophrenia: specific neurotransmitter systems. CNS Neurosci Ther 17:89–96

    Article  PubMed  Google Scholar 

  • Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776–786

    Article  PubMed  CAS  Google Scholar 

  • Howlett DR, Morris H, Nahorski SR (1979) Anomalous properties of [3H]-spiperone binding sites in various areas of the rat limbic system. Mol Phamacol 15:506–514

    CAS  Google Scholar 

  • Huff RM, Molinoff PB (1982) Quantitative determination of dopamine receptor subtypes not linked to activation of adenylate cyclase in rat striatum. Proc Natl Acad Sci USA 79:7561–7565

    Article  PubMed  CAS  Google Scholar 

  • Imafuku J (1987) The characterization of [3H]sulpiride binding sites in rat striatal membranes. Brain Res 402:331–338

    Article  PubMed  CAS  Google Scholar 

  • Insel PA, Stoolman LM (1978) Radioligand binding to beta adrenergic receptors of intact cultured S49 cells. Mol Phamacol 14:549–561

    CAS  Google Scholar 

  • Jackson DM, Westlinddanielsson A (1994) Dopamine receptors: molecular-biology, biochemistry and behavioral-aspects. Pharmacol Ther 64:291–370

    Article  PubMed  CAS  Google Scholar 

  • Juckel G, Friedel E, Koslowski M, Witthaus H, Ozgürdal S, Gudlowski Y, Knutson B, Wrase J, Brüne M, Heinz A, Schlagenhauf F (2012) Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia. Neuropsychobiology 66:50–56

    Article  PubMed  Google Scholar 

  • Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progr Neuropsychopharmacol Biol Psychiatry 27:1081–1090

    Article  CAS  Google Scholar 

  • Kenakin T (1997) Differences between natural and recombinant G protein-coupled receptor systems with varying receptor/G protein stoichiometry. Trends Pharmacol Sci 18:456–464

    PubMed  CAS  Google Scholar 

  • Kestler LP, Walker E, Vega EM (2001) Dopamine receptors in the brains of schizophrenia patients: a meta-analysis of the findings. Behav Pharmacol 12:355–371

    Article  PubMed  CAS  Google Scholar 

  • Kim DS, Szczypka MS, Palmiter RD (2000) Dopamine-deficient mice are hypersensitive to dopamine receptor agonists. J Neurosci 20:4405–4413

    PubMed  CAS  Google Scholar 

  • King MV, Seeman P, Marsden CA, Fone KCF (2009) Increased dopamine D2 high receptors in rats reared in social isolation. Synapse 63:476–483

    Article  PubMed  CAS  Google Scholar 

  • Kohler C, Hall H, Ogren SO, Gawell L (1985) Specific in vitro and in vivo binding of 3H-raclopride—a potent substituted benzamide drug with high-affinity for dopamine D-2 receptors in the rat brain. Biochem Pharmacol 34:2251–2259

    Article  PubMed  CAS  Google Scholar 

  • Laruelle M (1998) Imaging dopamine transmission in schizophrenia. Q J Nucl Med 42:211–221

    PubMed  CAS  Google Scholar 

  • Laruelle M, Abidargham A, Vandyck CH, Rosenblatt W, Zeaponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung HF, Innis RB (1995) Spect imaging of striatal dopamine release after amphetamine challenge. J Nucl Med 36:1182–1190

    PubMed  CAS  Google Scholar 

  • Laymon CM, Mason NS, Frankle WG, Carney JP, Lopresti BJ, Litschge MY, Mathis CA, Mountz JM, Narendran R (2009) Human biodistribution and dosimetry of the D2/3 agonist 11C-N-propylnorapomorphine (11C-NPA) determined from PET. J Nucl Med 50:814–817

    Article  PubMed  CAS  Google Scholar 

  • Lazareno S, Nahorski SR (1982) Selective labelling of dopamine D2 receptors in rat striatum by [3H]domperidone but not by [3H]spiperone. Eur J Pharmacol 81:273–285

    Article  PubMed  CAS  Google Scholar 

  • Lee T, Seeman P, Rajput A, Farley IJ, Hornykiewicz O (1978) Receptor basis for dopaminergic super-sensitivity in Parkinson's disease. Nature 273:59–61

    Article  PubMed  CAS  Google Scholar 

  • Levant B (2007) Characterization of dopamine receptors. In: Current protocols in pharmacology. 1.6.1-1.6.15. doi:10.1002/0471141755.ph0106s36

  • Levant B, Grigoriadis DE, Desouza EB (1992) Characterization of [3H]quinpirole binding to D2-like dopamine receptors in rat brain. J Pharmacol Exp Ther 262:929–935

    PubMed  CAS  Google Scholar 

  • Levesque D, Diaz J, Pilon C, Martres M-P, Giros B, Souil E, Schott D, Morgat J-L, Schwartz J-C, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydrox-N, N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 89:8155–8159

    Article  PubMed  CAS  Google Scholar 

  • Lipina TV, Niwa M, Jaaro-Peled H, Fletcher PJ, Seeman P, Sawa A, Roder JC (2010) Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. Genes Brain Behav 9:777–789

    Article  PubMed  CAS  Google Scholar 

  • Liu ISC, George SR, Seeman P (2000) The human dopamine D2longer receptor has a high-affinity state and inhibits adenylyl cyclase. Mol Brain Res 77:281–284

    Article  PubMed  CAS  Google Scholar 

  • Mackay AVP, Iversen LL, Rossor M, Spokes E, Bird E, Arregui A, Creese I, Snyder SH (1982) Increased brain dopamine and dopamine-receptors in schizophrenia. Arch Gen Psychiatry 39:991–997

    Article  PubMed  CAS  Google Scholar 

  • Malmberg A, Mohell N (1995) Characterization of [3H]quinpirole binding to human dopamine D2a and D3 receptors: effects of ions and guanine nucleotides. J Pharmacol Exp Ther 274:790–797

    PubMed  CAS  Google Scholar 

  • Marcellino D, Kehr J, Agnati LF, Fuxe K (2012) Increased affinity of dopamine for D2-like versus D1-like receptors. Relevance for volume transmission in interpreting PET findings. Synapse 66:196–203

    Article  PubMed  CAS  Google Scholar 

  • Martin GE, Williams M, Pettibone DJ, Zrada MM, Lotti VJ, Taylor DA, Jones JH (1985) Selectivity of (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] for dopamine receptors in vitro and in vivo. J Pharmacol Exp Ther 233:395–401

    PubMed  CAS  Google Scholar 

  • Mccormick PN, Kapur S, Seeman P, Wilson AA (2008) Dopamine D2 receptor radiotracers [11C](+)-PHNO and [3H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo. Nucl Med Biol 35:11–17

    Article  PubMed  CAS  Google Scholar 

  • Mccormick PN, Kapur S, Reckless G, Wilson AA (2009) Ex vivo [11C]-(+)-PHNO binding is unchanged in animal models displaying increased high-affinity states of the D2 receptor in vitro. Synapse 63:998–1009

    Article  PubMed  CAS  Google Scholar 

  • Mccormick PN, Ginovart N, Wilson AA (2011) Isoflurane anaesthesia differentially affects the amphetamine sensitivity of agonist and antagonist D2/D3 positron emission tomograph radiotracers: implications for in vivo imaging of dopamine release. Mol Imag Biol 13:737–746

    Article  Google Scholar 

  • Metwally KA, Dukat M, Egan CT, Smith C, Dupre A, Gauthier CB, Herrick-Davis K, Teitler M, Glennon RA (1998) Spiperone: influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 41:5084–5093

    Article  PubMed  CAS  Google Scholar 

  • Michel MC, Goepel M (1998) Differential alpha1-adrenoceptor labeling by [3H]prazosin and [3H]tamsulosin. Eur J Pharmacol 342:85–92

    Article  PubMed  CAS  Google Scholar 

  • Michel T, Hoffmann BB, Lefkowitz RJ (1980) Differential regulation of the alpha 2-adrenergic receptor by Na+ and guanine nucleotides. Nature 288:709–711

    Article  PubMed  CAS  Google Scholar 

  • Michel MC, Brodde OE, Schnepel B, Behrendt J, Tschada R, Motulsky HJ, Insel PA (1989) [3H] idazoxan and some other alpha 2-adrenergic drugs also bind with high-affinity to a nonadrenergic site. Mol Phamacol 35:324–330

    CAS  Google Scholar 

  • Mizrahi R, Agid O, Borlido C, Suridjan I, Rusjan P, Houle S, Remington G, Wilson AA, Kapur S (2011) Effects of antipsychotics on D3 receptors: a clinical pet study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. Schizophr Res 131:63–68

    Article  PubMed  Google Scholar 

  • Moncrieff J (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 114:3–13

    Article  PubMed  CAS  Google Scholar 

  • Morgante L, Colosimo C, Antonini A, Marconi R, Meco G, Pederzoli M, Pontieri FE, Cicarelli G, Abbruzzese G, Zappulla S, Ramat S, Manfredi M, Bottacchi E, Abrignani M, Berardelli A, Cozzolino A, Paradiso C, De Gaspari D, Morgante F, Barone P (2012) Psychosis associated to Parkinson’s disease in the early stages: relevance of cognitive decline and depression. J Neurol Neurosur PS 83:76–82

    Google Scholar 

  • Narendran R, Hwang D-R, Slifstein M, Hwang Y, Huang Y, Ekelund J, Guillin O, Scher E, Martinez D, Laruelle M (2005) Measurement of the proportin of D2 receptors configured in state of high affinity for agonists in vivo: a positron emission tomography study using [11C]N-propyl-norapomorphine and [11C]raclopride in baboons. J Pharmacol Exp Ther 315:80–90

    Article  PubMed  CAS  Google Scholar 

  • Narendran R, Slifstein M, Guilin O, Hwang Y, Hwang D-R, Scher E, Reeder S, Rabiner E, Laruelle M (2006) Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo. Synapse 60:485–495

    Article  PubMed  CAS  Google Scholar 

  • Narendran R, Mason NS, Laymon CM, Lopresti BJ, Velasquez ND, May MA, Kendro S, Martinez D, Mathis CA, Frankle WG (2010) A comparative evaluation of the dopamine D(2/3) agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum. J Pharmacol Exp Ther 333:533–539

    Article  PubMed  CAS  Google Scholar 

  • Narendran R, Martinez D, Mason NS, Lopresti BJ, Himes ML, Chen CM, May MA, Price JC, Mathis CA, Frankle WG (2011) Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study. Synapse 65:1344–1349

    Article  PubMed  CAS  Google Scholar 

  • Neumeyer JL, Gao YG, Kula NS, Baldessarini RJ (1990) Synthesis and dopamine receptor affinity of (R)-(-)-2-fluoro-N-n-propylnorapomorphine: a highly potent and selective dopamine D2 agonist. J Med Chem 33:3122–3124

    Article  PubMed  CAS  Google Scholar 

  • Niznik HB, Grigoriadis DE, Pribar I, Buchman O, Seeman P (1985) Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2. Naunyn-Schmiedeberg's Arch Pharmacol 329:333–343

    Article  CAS  Google Scholar 

  • Novak G, Seeman P (2010) Hyperactive mice show elevated D2(High) receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II alpha knockouts. Synapse 64:794–800

    PubMed  CAS  Google Scholar 

  • Novak G, Seeman P, Foll BL (2010) Exposure to nicotine produces an increase in dopamine D2(High) receptors: a possible mechanism for dopamine hypersensitivity. Int J Neurosci 120:691–697

    Article  PubMed  CAS  Google Scholar 

  • Ohba H, Harada N, Nishiyama S, Kakiuchi T, Tsukada H (2009) Ketamine/xylazine anesthesia alters [11C]MNPA binding to dopamine D2 receptors and response to methamphetamine challenge in monkey brain. Synapse 63:534–537

    Article  PubMed  CAS  Google Scholar 

  • Otsuka T, Ito H, Halldin C, Takahashi H, Takano H, Arakawa R, Okumura M, Kodaka F, Miyoshi M, Sekine M, Seki C, Nakao R, Suzuki K, Finnema S, Hirayasu Y, Suhara T, Farde L (2009) Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-n-propylnorapomorphine in the human brain. J Nucl Med 50:703–710

    Article  PubMed  CAS  Google Scholar 

  • Peng T, Zysk J, Dorff P, Elmore CS, Strom P, Malmquist J, Ding M, Tuke D, Werkheiser J, Widzowski D, Mrzljak L, Maier D (2010) D2 receptor occupancy in conscious rat brain is not significantly distinguished with [3H]-MNPA, [3H]-(+)-PHNO, and [3H]-raclopride. Synapse 64:624–633

    Article  PubMed  CAS  Google Scholar 

  • Perreault ML, Seeman P, Szechtman H (2007) Kappa-opioid receptor stimulation quickens pathogenesis of compulsive checking in the quinpirole sensitization model of obsessive-compulsive disorder (OCD). Behav Neurosci 121:976–991

    Article  PubMed  CAS  Google Scholar 

  • Perreault ML, Hasbi A, Alijaniaram M, Fan T, Varghese G, Fletcher PJ, Seeman P, O'dowd BF, George SR (2010) The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia. J Biol Chem 285:36625–36634

    Article  PubMed  CAS  Google Scholar 

  • Pittman RN, Molinoff PB (1980) Interactions of agonists and antagonists with beta-adrenergic receptors on intact L6 muscle cells. J Cyclic Nucleotide Res 6:421–435

    PubMed  CAS  Google Scholar 

  • Primus RJ, Thurkauf A, Xu J, Yevich E, Mcinerney S, Shaw K, Tallman JF, Gallager DW (1997) II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. J Pharmacol Exp Ther 282:1020–1027

    PubMed  CAS  Google Scholar 

  • Qin K, Dong CM, Wu GY, Lambert NA (2011) Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers. Nat Chem Biol 7:740–747

    Article  PubMed  CAS  Google Scholar 

  • Richfield EK, Young AB, Penney JB (1986) Properties of D2 dopamine receptor autoradiography: high percentage of high-affinity agonist sites and increased nucleotide sensitivity in tissue sections. Brain Res 383:121–128

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    Article  PubMed  CAS  Google Scholar 

  • Ross SB (1995) Heterogenous binding of 3H-remoxipride to membranes of rat liver and brain. Pharmacol Toxicol 76:29–35

    Article  PubMed  CAS  Google Scholar 

  • Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S (2007) "Breakthrough'' dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 27:2979–2986

    Article  PubMed  CAS  Google Scholar 

  • Searle G, Beaver JD, Comley RA, Bani M, Tziortzi A, Slifstein M, Mugnaini M, Griffante C, Wilson AA, Merlo-Pich E, Houle S, Gunn R, Rabiner EA, Laruelle M (2010) Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry 68:392–399

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (2008) Dopamine D2(High) receptors on intact cells. Synapse 62:314–318

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (2009) Dopamine D2High receptors measured ex vivo are elevated in amphetamine-sensitized animals. Synapse 63:186–192

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (2011) All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors. CNS Neurosci Ther 17:118–132

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (2012) Dopamine agonist radioligand binds to both D2High and D2Low receptors, explaining why alterations in D2High are not detected in human brain scans. Synapse 66:88–93

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Lee T, Chauwong M, Tedesco J, Wong K (1976) Dopamine receptors in human and calf brains, using [3H]apomorphine and an antipsychotic drug. Proc Natl Acad Sci U S A 73:4354–4358

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Watanabe M, Grigoriadis D, Tedesco JL, George SR, Svensson U, Nilsson JLG, Neumeyer JL (1985) Dopamine D2 receptor-binding sites for agonists—a tetrahedral model. Mol Phamacol 28:391–399

    CAS  Google Scholar 

  • Seeman P, Guan HC, Civelli O, Vantol HHM, Sunahara RK, Niznik HB (1992) The cloned dopamine D2 receptor reveals different densities for dopamine receptor antagonist ligands: implications for human brain positron emission tomography. Eur J Pharmacol 227:139–146

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Tallerico T, Ko F (2003) Dopamine displaces [3H]domperidone from high-affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: implications for human positron emission tomography. Synapse 49:209–215

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Weinshenker D, Quirion R, Srivastava IAK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T (2005) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci USA 102:3513–3518

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, Mcknight GS, Roder JC (2006) Psychosis pathways converge via D2high dopamine receptors. Synapse 60:319–346

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Hall FS, Uhl G (2007a) Increased dopamine D2High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity. Synapse 61:573–576

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Mccormick PN, Kapur S (2007b) Increased dopamine D2(High) receptors in amphetamine-sensitized rats, measured by the agonist [3H](+)PHNO. Synapse 61:263–267

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, Battaglia G, Corti C, Corsi M, Brun V (2009) Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(High) receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse 63:247–251

    Article  PubMed  CAS  Google Scholar 

  • Seneca N, Finnema SJ, Farde L, Gulyas B, Wikström HV, Halldin C, Innis RB (2006) Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride. Synapse 59:260–269

    Article  PubMed  CAS  Google Scholar 

  • Shotbolt P, Tziortzi AC, Searle GE, Colasanti A, Van Der Aart J, Abanades S, Plisson C, Miller SR, Huiban M, Beaver JD, Gunn RN, Laruelle M, Rabiner EA (2012) Within-subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute amphetamine challenge in healthy humans. J Cerebr Blood Flow Metabol 32:127–136

    Article  CAS  Google Scholar 

  • Shuto T, Seeman P, Kuroiwa M, Nishi A (2008) Repeated administration of a dopamine D1 receptor agonist reverses the increased proportions of striatal dopamine D1High and D2High receptors in methamphetamine-sensitized rats. Eur J Neursoci 27:2551–2557

    Article  Google Scholar 

  • Sibley DR, Creese I (1983) Regulation of ligand-binding to pituitary D-2 dopaminergic receptors. Effects of divalent cations and functional group modification. J Biol Chem 258:4957–4965

    PubMed  CAS  Google Scholar 

  • Sibley DR, De Lean A, Creese I (1982) Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor. J Biol Chem 257:6351–6361

    PubMed  CAS  Google Scholar 

  • Sibley DR, Mahan LC, Creese I (1983) Dopamine receptor binding on intact cells. Absence of a high-affinity agonist-receptor binding state Mol Phamacol 23:295–302

    CAS  Google Scholar 

  • Simola N, Morelli M, Seeman P (2008) Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects. Synapse 62:394–397

    Article  PubMed  CAS  Google Scholar 

  • Skinbjerg M, Namkung Y, Halldin C, Innis RB, Sibley DR (2009) Pharmacological characterization of 2-methoxy-N-propylnorapomorphine's interactions with D2 And D3 dopamine receptors. Synapse 63:462–475

    Article  PubMed  CAS  Google Scholar 

  • Skinbjerg M, Liow JS, Seneca N, Hong J, Lu S, Thorsell A, Heilig M, Pike VW, Halldin C, Sibley DR, Innis RB (2010a) D2 receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model. Neuroimage 50:1402–1407

    Article  PubMed  CAS  Google Scholar 

  • Skinbjerg M, Seneca N, Liow JS, Hong JS, Weinshenker D, Pike VW, Halldin C, Sibley DR, Innis RB (2010b) Dopamine beta-hydroxylase-deficient mice have normal densities of D(2) dopamine receptors in the high-affinity state based on in vivo PET imaging and in vitro radioligand binding. Synapse 64:699–703

    PubMed  CAS  Google Scholar 

  • Skinbjerg M, Sibley DR, Javitch JA, Abi-Dargham A (2012) Imaging the high-affinity state of the dopamine D2 receptor in vivo: fact or fiction? Biochem Pharmacol 83:193–198

    Article  PubMed  CAS  Google Scholar 

  • Sokoloff P, Martres MP, Delandre M, Redouane K, Schwartz JC (1984) 3H-domperidone binding sites differ in rat striatum and pituitary. Naunyn-Schmiedeberg's Arch Pharmacol 327:221–227

    Article  CAS  Google Scholar 

  • Strange PG (2008) Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. Br J Pharmacol 153:1353–1363

    Article  PubMed  CAS  Google Scholar 

  • Sumiyoshi T, Seeman P, Uehara T, Itoh H, Tsunoda M, Kurachi M (2005) Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia. Mol Brain Res 140:116–119

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Ginovart N, Ko F, Seeman P, Kapur S (2003) In vivo evidence for dopamine-mediated internalization of D2-receptors after amphetamine: differential findings with [3H]raclopride versus [3H]spiperone. Mol Phamacol 63456-63462

  • Tassin JP, Torrens Y, Salomon L, Lanteri C, Seeman P (2007) Elevated dopamine D2High receptors in alpha-1b-adrenoceptor knockout supersensitive mice. Synapse 61:569–572

    Article  PubMed  CAS  Google Scholar 

  • Teeter MM, Froimowitz M, Stec B, Durand CJ (1994) Homology modeling of the dopamine D2 receptor and its testing by docking of agonists and tricyclic antagonists. J Med Chem 37:2874–2888

    Article  PubMed  CAS  Google Scholar 

  • Tian WN, Deth RC (1993) Precoupling of Gi/G(o)-linked receptors and its allosteric regulation by monovalent cations. Life Sci 52:1899–1907

    Article  PubMed  CAS  Google Scholar 

  • Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, Laruelle M, Rabiner EA, Gunn RN (2011) Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage 54:264–277

    Article  PubMed  CAS  Google Scholar 

  • Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, Lemeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203

    Article  PubMed  CAS  Google Scholar 

  • Van Der Weide J, De Vries JB, Tepper PG, Horn AS (1987) The effects of kainic acid and 6-hydroxdopamine lesions, metal ions and GTP on in vitro binding of the D-2 dopamine agonist, [3H]N-0437, to striatal membranes. Eur J Pharmacol 143:101–107

    Article  PubMed  Google Scholar 

  • Van Vliet LA, Rodenhuis N, Dijkstra D, Wikstrom H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Sundell S, Lundmark M (2000) Synthesis and pharmacological evaluation of thiopyran analogues of the dopamine D3 receptor-selective agonist (4aR,10bR)-(+)-trans-3,4,4a,10b-tetrahydro-4-n-Propyl-2H,5H-[1]b enzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907). J Med Chem 43:2871–2882

    Article  PubMed  CAS  Google Scholar 

  • Verstappen CCP, Bloem BR, Haaxma CA, Oyen WJG, Horstink MWIM (2007) Diagnostic value of asymmetric striatal D-2 receptor upregulation in Parkinson’s disease: an [123I]IBZM and [123I]FP-CIT SPECT study. Eur J Nucl Med Mol Imag 34:502–507

    Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004) Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 9:557–569

    Article  PubMed  CAS  Google Scholar 

  • Watanabe M, George SR, Seeman P (1985) Dependence of dopamine receptor conversion from agonist high- to low-affinity state on temperature and sodium ions. Biochem Pharmacol 34:2459–2463

    Article  PubMed  CAS  Google Scholar 

  • Willeit M, Ginovart N, Kapur S, Houle S, Hussey D, Seeman P, Wilson AA (2006) High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO. Biol Psychiatry 59:389–394

    Article  PubMed  CAS  Google Scholar 

  • Willeit M, Ginovart N, Graff A, Rusjan P, Vitcu I, Houle S, Seeman P, Wilson AA, Kapur S (2008) First human evidence of D-amphetamine induced displacement of a D2/3 agonist radioligand: a [11C]-(+)-PHNO positron emission tomography study. Neuropsychopharmacology 33:279–289

    Article  PubMed  CAS  Google Scholar 

  • Williams DR, Lees AJ (2005) Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. The Lancet Neurology 4:605–610

    Google Scholar 

  • Wilson J, Lin H, Fu DY, Javitch JA, Strange PG (2001) Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation. J Neurochem 77:493–504

    Article  PubMed  CAS  Google Scholar 

  • Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP (2007) The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav 6:628–639

    Article  PubMed  CAS  Google Scholar 

  • Wreggett KA, Seeman P (1984) Agonist high- and low-affinity states of the D2-dopamine receptor in calf brain. Partial conversion by guanine nucleotide Mol Phamacol 25:10–17

    CAS  Google Scholar 

  • Yang M, Verfurth F, Buscher R, Michel MC (1997) Is alpha1D-adrenoceptor protein detectable in rat tissues? Naunyn-Schmiedeberg's Arch Pharmacol 355:438–446

    Article  CAS  Google Scholar 

  • Zakzanis KK, Hansen KT (1998) Dopamine D2 densities and the schizophrenic brain. Schizophr Res 32:201–206

    Article  PubMed  CAS  Google Scholar 

  • Zawarynski P, Tallerico T, Seeman P, Lee SP, O'dowd BF, George SR (1998) Dopamine D2 receptor dimers in human and rat brain. Febs Lett 441:383–386

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Work in the authors’ lab has been supported by a grant from the Dutch Technology Foundation STW (grant 10127).

Conflict of interest

MCM is an employee of Boehringer Ingelheim, a company marketing the D2 agonist pramipexole.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Jan-Peter van Wieringen & Jan Booij

  2. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Vladimir Shalgunov & Philip Elsinga

  3. Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany

    Martin C. Michel

  4. Institut für Pharmakologie, Johannes Gutenberg Universität, Obere Zahlbacher Str. 67, 55101, Mainz, Germany

    Martin C. Michel

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  1. Jan-Peter van Wieringen
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  2. Jan Booij
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  5. Martin C. Michel
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Correspondence to Martin C. Michel.

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van Wieringen, JP., Booij, J., Shalgunov, V. et al. Agonist high- and low-affinity states of dopamine D2 receptors: methods of detection and clinical implications. Naunyn-Schmiedeberg's Arch Pharmacol 386, 135–154 (2013). https://doi.org/10.1007/s00210-012-0817-0

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