Psychopharmacology

, Volume 180, Issue 4, pp 705–715 | Cite as

Mapping dopamine D2/D3 receptor function using pharmacological magnetic resonance imaging

  • Yin-Ching I. Chen
  • Ji-Kyung Choi
  • Susan L. Andersen
  • Bruce R. Rosen
  • Bruce G. Jenkins
Original Investigation

Abstract

Rationale

Regulation of dopamine release and synthesis occurs via pre-synaptic dopamine (DA) D2/D3 autoreceptors (DARs). Mapping of DAR function in vivo is difficult and is usually best assessed using invasive measures of DA release, such as microdialysis at discrete sites. We wished to show that pharmacological magnetic resonance imaging (phMRI) may prove useful for this purpose.

Objective

To demonstrate that the relative cerebral blood volume (rCBV) changes induced by amphetamine can be modulated by DA D2 receptor antagonists and agonists in a manner consistent with modulation of DAR function and to compare these effects with microdialysis.

Methods

We used phMRI with iron oxide contrast agents to map changes in rCBV in response to an amphetamine challenge, pre-treatment and post-treatment with varying doses of the D2 antagonist eticlopride and the D2 agonist quinpirole. We also compared the effects of D2 antagonism using microdialysis measurements of DA release.

Results

Antagonism of D2 receptors with eticlopride potentiated rCBV changes induced by amphetamine in the nucleus accumbens and caudate putamen in a dose-dependent manner. The amphetamine-induced increase in rCBV in the accumbens in animals pre-treated with eticlopride was paralleled by a similar percentage increase in DA release measured by means of microdialysis. Conversely, agonism of D2 receptors using quinpirole reduced amphetamine-induced rCBV changes in the caudate putamen and nucleus accumbens. The effects of both quinpirole and eticlopride on amphetamine-induced rCBV changes were largest in the nucleus accumbens.

Conclusions

These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.

Keywords

Dopamine Autoreceptor MRI Amphetamine Nucleus accumbens Microdialysis Eticlopride Quinpirole Relative cerebral blood volume D2 

References

  1. Andersen SL, Gazzara RA (1994) The development of D2 autoreceptor-mediated modulation of K(+)-evoked dopamine release in the neostriatum. Brain Res Dev Brain Res 78:123–130CrossRefPubMedGoogle Scholar
  2. Booze RM, Wallace DR (1995) Dopamine D2 and D3 receptors in the rat striatum and nucleus accumbens: use of 7-OH-DPAT and [125I]-iodosulpride. Synapse 19:1–13CrossRefPubMedGoogle Scholar
  3. Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564:203–219CrossRefPubMedGoogle Scholar
  4. Breiter H, Gollub R, Weisskoff R, Kennedy D, Makris N, Berke J, Goodman J, Kantor R, Gastfriend D, Riorden J, Mathew R, Rosen B, Hyman S (1997) Acute effects of cocaine on human brain activity and emotion. Neuron 19:591–611CrossRefPubMedGoogle Scholar
  5. Cass WA, Gerhardt GA, Mayfield RD, Curella P, Zahniser NR (1992) Differences in dopamine clearance and diffusion in rat striatum and nucleus accumbens following systemic cocaine administration. J Neurochem 59:259–266PubMedCrossRefGoogle Scholar
  6. Chen Q, Andersen AH, Zhang Z, Ovadia A, Gash DM, Avison MJ (1996) Mapping drug-induced changes in cerebral R2* by multiple gradient recalled echo functional MRI. Magn Reson Imaging 14:469–476CrossRefPubMedGoogle Scholar
  7. Chen YI, Galpern WR, Brownell AL, Matthews RT, Bogdanov M, Isacson O, Beal MF, Rosen BR, Jenkins BG (1997) Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data. Magn Reson Med 38:389–398PubMedCrossRefGoogle Scholar
  8. Chen YI, Brownell AL, Galpern W, Isacson O, Bogdanov M, Beal MF, Livni E, Rosen BR, Jenkins BG (1999) Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment. Neuroreport 10:2881–2886PubMedCrossRefGoogle Scholar
  9. Chen YC, Mandeville JB, Nguyen TV, Talele A, Cavagna F, Jenkins BG (2001) Improved mapping of pharmacologically induced neuronal activation using the IRON technique with superparamagnetic blood pool agents. J Magn Reson Imaging 14:517–524CrossRefPubMedGoogle Scholar
  10. Christian BT, Narayanan T, Shi B, Morris ED, Mantil J, Mukherjee J (2004) Measuring the in vivo binding parameters of [18F]-fallypride in monkeys using a PET multiple-injection protocol. J Cereb Blood Flow Metab 24:309–322CrossRefPubMedGoogle Scholar
  11. Cooper JR, Bloom FE, Roth RH (2003) The biochemical basis of neuropharmacology, 8th edn. Oxford University Press, OxfordGoogle Scholar
  12. Cory-Slechta DA, Widzowski DV, Pokora MJ (1993) Functional alterations in dopamine systems assessed using drug discrimination procedures. Neurotoxicology 14:105–114PubMedGoogle Scholar
  13. Dubowitz DJ, Bernheim KA, Chen DY, Bradley WG Jr, Andersen RA (2001) Enhancing fMRI contrast in awake-behaving primates using intravascular magnetite dextran nanoparticles. Neuroreport 12:2335–2340CrossRefPubMedGoogle Scholar
  14. Endres CJ, Kolachana BS, Saunders RC, Su T, Weinberger D, Breier A, Eckelman WC, Carson RE (1997) Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies. J Cereb Blood Flow Metab 17:932–942CrossRefPubMedGoogle Scholar
  15. Furmidge L, Tong ZY, Petry N, Clark D (1991) Effects of low, autoreceptor selective doses of dopamine agonists on the discriminative cue and locomotor hyperactivity produced by d-amphetamine. J Neural Transm Gen Sect 86:61–70CrossRefPubMedGoogle Scholar
  16. Garris PA, Wightman RM (1994) Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci 14:442–450PubMedGoogle Scholar
  17. Glick SD, Rossman K, Wang S, Dong N, Keller RW Jr (1993) Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with d-amphetamine. Brain Res 628:201–208CrossRefPubMedGoogle Scholar
  18. Guix T, Hurd YL, Ungerstedt U (1992) Amphetamine enhances extracellular concentrations of dopamine and acetylcholine in dorsolateral striatum and nucleus accumbens of freely moving rats. Neurosci Lett 138:137–140CrossRefPubMedGoogle Scholar
  19. Hamilton WC (1965) Significance tests on the crystallographic R factor. Acta Crystallogr 18:502–510CrossRefGoogle Scholar
  20. Han S, Rowell PP, Carr LA (1999) D2 autoreceptors are not involved in the down-regulation of the striatal dopamine transporter caused by alpha-methyl-p-tyrosine. Res Commun Mol Pathol Pharmacol 104:331–338PubMedGoogle Scholar
  21. Innis RB, Malison RT, al-Tikriti M, Hoffer PB, Sybirska EH, Seibyl JP, Zoghbi SS, Baldwin RM, Laruelle M, Smith EO et al (1992) Amphetamine-stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates. Synapse 10:177–184CrossRefPubMedGoogle Scholar
  22. Jenkins BG, Armstrong E, Lauffer RB (1991) Site-specific water proton relaxation enhancement of iron(III) chelates noncovalently bound to human serum albumin. Magn Reson Med 17:164–178PubMedCrossRefGoogle Scholar
  23. Jenkins BG, Chen YI, Mandeville JB (2002) Pharmacologic magnetic resonance imaging (phMRI). In: van Bruggen N, Roberts T (eds) Biomedical imaging in experimental neuroscience. CRC, Boca Raton, pp 155–209Google Scholar
  24. Joseph JD, Wang YM, Miles PR, Budygin EA, Picetti R, Gainetdinov RR, Caron MG, Wightman RM (2002) Dopamine autoreceptor regulation of release and uptake in mouse brain slices in the absence of D(3) receptors. Neuroscience 112:39–49CrossRefPubMedGoogle Scholar
  25. Kalivas PW, Duffy P (1991) A comparison of axonal and somatodendritic dopamine release using in vivo dialysis. J Neurochem 56:961–967PubMedCrossRefGoogle Scholar
  26. Kennan RP, Scanley BE, Innis RB, Gore JC (1998) Physiological basis for BOLD MR signal changes due to neuronal stimulation: separation of blood volume and magnetic susceptibility effects. Magn Reson Med 40:840–846PubMedCrossRefGoogle Scholar
  27. Kennedy RT, Jones SR, Wightman RM (1992) Dynamic observation of dopamine autoreceptor effects in rat striatal slices. J Neurochem 59:449–455PubMedCrossRefGoogle Scholar
  28. Khan ZU, Gutierrez A, Martin R, Penafiel A, Rivera A, De La Calle A (1998) Differential regional and cellular distribution of dopamine D2-like receptors: an immunocytochemical study of subtype-specific antibodies in rat and human brain. J Comp Neurol 402:353–371CrossRefPubMedGoogle Scholar
  29. Koeltzow TE, Xu M, Cooper DC, Hu XT, Tonegawa S, Wolf ME, White FJ (1998) Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice. J Neurosci 18:2231–2238PubMedGoogle Scholar
  30. Kuczenski R, Segal DS (1999) Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate. Psychopharmacology (Berl) 147:96–103CrossRefGoogle Scholar
  31. Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451PubMedCrossRefGoogle Scholar
  32. Lehmann J, Briley M, Langer SZ (1983) Characterization of dopamine autoreceptor and [3H]spiperone binding sites in vitro with classical and novel dopamine receptor agonists. Eur J Pharmacol 88:11–26CrossRefPubMedGoogle Scholar
  33. Li SJ, Biswal B, Li Z, Risinger R, Rainey C, Cho JK, Salmeron BJ, Stein EA (2000) Cocaine administration decreases functional connectivity in human primary visual and motor cortex as detected by functional MRI. Magn Reson Med 43:45–51CrossRefPubMedGoogle Scholar
  34. Mandeville JB, Marota JJ, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR, Weisskoff RM (1998) Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med 39:615–624PubMedCrossRefGoogle Scholar
  35. Mandeville JB, Jenkins BG, Kosofsky BE, Moskowitz MA, Rosen BR, Marota JJ (2001) Regional sensitivity and coupling of BOLD and CBV changes during stimulation of rat brain. Magn Reson Med 45:443–447CrossRefPubMedGoogle Scholar
  36. Marota JJ, Mandeville JB, Weisskoff RM, Moskowitz MA, Rosen BR, Kosofsky BE (2000) Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in Rat. Neuroimage 11:13–23CrossRefPubMedGoogle Scholar
  37. Missale C, Castelletti L, Govoni S, Spano PF, Trabucchi M, Hanbauer I (1985) Dopamine uptake is differentially regulated in rat striatum and nucleus accumbens. J Neurochem 45:51–56PubMedCrossRefGoogle Scholar
  38. Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA (2002) Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 5:169–174CrossRefPubMedGoogle Scholar
  39. Nguyen TV, Brownell AL, Iris Chen YC, Livni E, Coyle JT, Rosen BR, Cavagna F, Jenkins BG (2000) Detection of the effects of dopamine receptor supersensitivity using pharmacological MRI and correlations with PET. Synapse 36:57–65CrossRefPubMedGoogle Scholar
  40. Olsson H, Halldin C, Farde L (2004) Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 22:794–803CrossRefPubMedGoogle Scholar
  41. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  42. Pehek EA (1999) Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum. J Pharmacol Exp Ther 289:14–23PubMedGoogle Scholar
  43. Phillips PE, Hancock PJ, Stamford JA (2002) Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release. Synapse 44:15–22CrossRefPubMedGoogle Scholar
  44. Rayevsky KS, Gainetdinov RR, Grekhova TV, Sotnikova TD (1995) Regulation of dopamine release and metabolism in rat striatum in vivo: effects of dopamine receptor antagonists. Prog Neuropsychopharmacol Biol Psychiatry 19:1285–1303CrossRefPubMedGoogle Scholar
  45. Robertson GS, Tham CS, Wilson C, Jakubovic A, Fibiger HC (1993) In vivo comparisons of the effects of quinpirole and the putative presynaptic dopaminergic agonists B-HT 920 and SND 919 on striatal dopamine and acetylcholine release. J Pharmacol Exp Ther 264:1344–1351PubMedGoogle Scholar
  46. Santiago M, Westerink BH (1991) The regulation of dopamine release from nigrostriatal neurons in conscious rats: the role of somatodendritic autoreceptors. Eur J Pharmacol 204:79–85CrossRefPubMedGoogle Scholar
  47. Schmitz Y, Schmauss C, Sulzer D (2002) Altered dopamine release and uptake kinetics in mice lacking D2 receptors. J Neurosci 22:8002–8009PubMedGoogle Scholar
  48. Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97PubMedGoogle Scholar
  49. Shen T, Weissleder R, Papisov M, Bogdanov A Jr, Brady TJ (1993) Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 29:599–604PubMedCrossRefGoogle Scholar
  50. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151CrossRefPubMedGoogle Scholar
  51. Stamford JA, Kruk ZL, Millar J (1988) Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study. Br J Pharmacol 94:924–932PubMedGoogle Scholar
  52. Stein EA (2001) fMRI: a new tool for the in vivo localization of drug actions in the brain. J Anal Toxicol 25:419–424PubMedGoogle Scholar
  53. Tang L, Todd RD, O’Malley KL (1994) Dopamine D2 and D3 receptors inhibit dopamine release. J Pharmacol Exp Ther 270:475–479PubMedGoogle Scholar
  54. Tidey JW, Bergman J (1998) Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs. J Pharmacol Exp Ther 285:1163–1174PubMedGoogle Scholar
  55. Villringer A, Rosen BR, Belliveau JW, Acerman JL, Lauffer RB, Buxton RB, Chao YS, Wedeen VJ, Brady TJ (1988) Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects. Magn Reson Med 6:164–174PubMedCrossRefGoogle Scholar
  56. Volkow ND, Fowler JS, Wang GJ (1999) Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans. J Psychopharmacol 13:337–345PubMedCrossRefGoogle Scholar
  57. Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, Gifford A, Wong C, Pappas N (2001) Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 158:2015–2021CrossRefPubMedGoogle Scholar
  58. Wechsler LR, Savaki HE, Sokoloff L (1979) Effects of d- and l-amphetamine on local cerebral glucose utilization in the conscious rat. J Neurochem 32:15–22PubMedCrossRefGoogle Scholar
  59. Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L (1990) Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 175:489–493PubMedGoogle Scholar
  60. Widzowski DV, Cory-Slechta DA (1993) Apparent mediation of the stimulus properties of a low dose of quinpirole by dopaminergic autoreceptors. J Pharmacol Exp Ther 266:526–534PubMedGoogle Scholar
  61. Wu Q, Reith ME, Kuhar MJ, Carroll FI, Garris PA (2001) Preferential increases in nucleus accumbens dopamine after systemic cocaine administration are caused by unique characteristics of dopamine neurotransmission. J Neurosci 21:6338–6347PubMedGoogle Scholar
  62. Wu Q, Reith ME, Walker QD, Kuhn CM, Carroll FI, Garris PA (2002) Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study. J Neurosci 22:6272–6281PubMedGoogle Scholar
  63. Zaharchuk G, Mandeville JB, Bogdanov AA Jr, Weissleder R, Rosen BR, Marota JJ (1999) Cerebrovascular dynamics of autoregulation and hypoperfusion. An MRI study of CBF and changes in total and microvascular cerebral blood volume during hemorrhagic hypotension. Stroke 30:2197–2204 (discussion 2204–2205)PubMedGoogle Scholar
  64. Zhang Z, Andersen A, Grondin R, Barber T, Avison R, Gerhardt G, Gash D (2001) Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake rhesus monkeys. Neuroimage 14:1159–1167CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Yin-Ching I. Chen
    • 1
  • Ji-Kyung Choi
    • 1
  • Susan L. Andersen
    • 2
  • Bruce R. Rosen
    • 1
  • Bruce G. Jenkins
    • 1
  1. 1.Athinoula A. Martinos Center for Biomedical Imaging and MGH-NMR CenterDepartment of Radiology Massachusetts General HospitalCharlestownUSA
  2. 2.Department of PsychiatryMcLean HospitalBelmontUSA

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