Top

EJNMMI Research

Published in:

Open Access 01-12-2013 | Original research

High correlation between in vivo [¹²³I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

Authors: Susanne Bäck, Mari Raki, Raimo K Tuominen, Atso Raasmaja, Kim Bergström, Pekka T Männistö

Published in: EJNMMI Research | Issue 1/2013

Abstract

Background

6-Hydroxydopamine (6-OHDA) is widely used in pre-clinical animal studies to induce degeneration of midbrain dopamine neurons to create animal models of Parkinson's disease. The aim of our study was to evaluate the potential of combined single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of differences in 6-OHDA-induced partial lesions in a dose- and time-dependent manner using the dopamine transporter (DAT) ligand 2β-carbomethoxy-3β-(4-[¹²³I]iodophenyl)tropane ([¹²³I]β-CIT).

Methods

Rats were unilaterally lesioned with intrastriatal injections of 8 or 2 × 10 μg 6-OHDA. At 2 or 4 weeks post-lesion, 40 to 50 MBq [¹²³I]β-CIT was administered intravenously and rats were imaged with small-animal SPECT/CT under isoflurane anesthesia. The striatum was delineated and mean striatal activity in the lesioned side was compared to the intact side. After the [¹²³I]β-CIT SPECT/CT scan, the rats were tested for amphetamine-induced rotation asymmetry, and their brains were immunohistochemically stained for DAT and tyrosine hydroxylase (TH). The fiber density of DAT- and TH-stained striata was estimated, and TH-immunoreactive cells in the rat substantia nigra pars compacta (SNpc) were stereologically counted.

Results

The striatal uptake of [¹²³I]β-CIT differed significantly between the lesion groups and the results were highly correlated to both striatal DAT- and TH-immunoreactive fiber densities and to TH-immunoreactive cell numbers in the rat SNpc. No clear progression of the lesion could be seen.

Conclusions

[¹²³I]β-CIT SPECT/CT is a valuable tool in predicting the condition of the rat midbrain dopaminergic pathway in the unilateral partial 6-OHDA lesion model of Parkinson's disease and it offers many advantages, allowing repeated non-invasive analysis of living animals.

Available only for authorised users

Dauer W, Przedborski S: Parkinson's disease: mechanisms and models. Neuron 2003, 39: 889–909. 10.1016/S0896-6273(03)00568-3CrossRefPubMed

Ungerstedt U: 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968, 5: 107–110. 10.1016/0014-2999(68)90164-7CrossRefPubMed

Ungerstedt U, Arbuthnott GW: Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 1970, 24: 485–493. 10.1016/0006-8993(70)90187-3CrossRefPubMed

Schwarting RK, Huston JP: The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 1996, 50: 275–331. 10.1016/S0301-0082(96)00040-8CrossRefPubMed

Schwarting RK, Huston JP: Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae. Prog Neurobiol 1996, 49: 215–266. 10.1016/S0301-0082(96)00015-9CrossRefPubMed

Kirik D, Rosenblad C, Björklund A: Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 1998, 152: 259–277. 10.1006/exnr.1998.6848CrossRefPubMed

Deumens R, Blokland A, Prickaerts J: Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 2002, 175: 303–317. 10.1006/exnr.2002.7891CrossRefPubMed

Sauer H, Oertel WH: Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 1994, 59: 401–415. 10.1016/0306-4522(94)90605-XCrossRefPubMed

Neumeyer JL, Wang SY, Milius RA, Baldwin RM, Zea-Ponce Y, Hoffer PB, Sybirska E, al-Tikriti M, Charney DS, Malison RT: [¹²³ I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane: high-affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 1991, 34: 3144–3146. 10.1021/jm00114a027CrossRefPubMed

10.

Innis RB, Seibyl JP, Scanley BE, Laruelle M, Abi-Dargham A, Wallace E, Baldwin RM, Zea-Ponce Y, Zoghbi S, Wang S: Single photon emission computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson disease. Proc Natl Acad Sci U S A 1993, 90: 11965–11969. 10.1073/pnas.90.24.11965PubMedCentralCrossRefPubMed

11.

Cass WA, Zahniser NR, Flach KA, Gerhardt GA: Clearance of exogenous dopamine in rat dorsal striatum and nucleus accumbens: role of metabolism and effects of locally applied uptake inhibitors. J Neurochem 1993, 61: 2269–2278. 10.1111/j.1471-4159.1993.tb07469.xCrossRefPubMed

12.

Lorang D, Amara SG, Simerly RB: Cell-type-specific expression of catecholamine transporters in the rat brain. J Neurosci 1994, 14: 4903–4914.PubMed

13.

Booij J, de Bruin K, Habraken JB, Voorn P: Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography. Eur J Nucl Med 2002, 29: 1221–1224. 10.1007/s00259-002-0845-yCrossRef

14.

Scherfler C, Donnemiller E, Schocke M, Dierkes K, Decristoforo C, Oberladstatter M, Kolbitsch C, Zschiegner F, Riccabona G, Poewe W, Wenning G: Evaluation of striatal dopamine transporter function in rats by in vivo beta-[¹²³ I]CIT pinhole SPECT. NeuroImage 2002, 17: 128–141. 10.1006/nimg.2002.1158CrossRefPubMed

15.

Van Camp N, Vreys R, Van Laere K, Lauwers E, Beque D, Verhoye M, Casteels C, Verbruggen A, Debyser Z, Mortelmans L, Sijbers J, Nuyts J, Baekelandt V, Van der Linden A: Morphologic and functional changes in the unilateral 6-hydroxydopamine lesion rat model for Parkinson's disease discerned with microSPECT and quantitative MRI. MAGMA 2010, 23: 65–75. 10.1007/s10334-010-0198-7CrossRefPubMed

16.

Hume SP, Lammertsma AA, Myers R, Rajeswaran S, Bloomfield PM, Ashworth S, Fricker RA, Torres EM, Watson I, Jones T: The potential of high-resolution positron emission tomography to monitor striatal dopaminergic function in rat models of disease. J Neurosci Methods 1996, 67: 103–112.PubMed

17.

Chen YC, Galpern WR, Brownell AL, Matthews RT, Bogdanov M, Isacson O, Keltner JR, Beal MF, Rosen BR, Jenkins BG: Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data. Magn Reson Med 1997, 38: 389–398. 10.1002/mrm.1910380306CrossRefPubMed

18.

Nguyen TV, Brownell AL, Iris Chen YC, Livni E, Coyle JT, Rosen BR, Cavagna F, Jenkins BG: Detection of the effects of dopamine receptor supersensitivity using pharmacological MRI and correlations with PET. Synapse 2000, 36: 57–65. 10.1002/(SICI)1098-2396(200004)36:1<57::AID-SYN6>3.0.CO;2-KCrossRefPubMed

19.

Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O: Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 2002, 15: 991–998. 10.1046/j.1460-9568.2002.01938.xCrossRefPubMed

20.

Inaji M, Okauchi T, Ando K, Maeda J, Nagai Y, Yoshizaki T, Okano H, Nariai T, Ohno K, Obayashi S, Higuchi M, Suhara T: Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats. Brain Res 2005, 1064: 136–145. 10.1016/j.brainres.2005.09.055CrossRefPubMed

21.

Pellegrino D, Cicchetti F, Wang X, Zhu A, Yu M, Saint-Pierre M, Brownell AL: Modulation of dopaminergic and glutamatergic brain function: PET studies on parkinsonian rats. J Nucl Med 2007, 48: 1147–1153. 10.2967/jnumed.106.037796CrossRefPubMed

22.

Zhu A, Wang X, Yu M, Wang JQ, Brownell AL: Evaluation of four pyridine analogs to characterize 6-OHDA-induced modulation of mGluR5 function in rat brain using microPET studies. J Cereb Blood Flow Metab 2007, 27: 1623–1631. 10.1038/sj.jcbfm.9600461CrossRefPubMed

23.

Nikolaus S, Larisch R, Vosberg H, Beu M, Hautzel H, Wirrwar A, Mueller HW, Antke C: In vivo imaging neurotransmitter function. The rat 6-hydroxydopamine model and its relevance for human Parkinson's disease. Nuklearmedizin 2011, 50: 155–166. 10.3413/Nukmed-0371-10-12CrossRefPubMed

24.

Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press; 1997.

25.

Kyono K, Takashima T, Katayama Y, Kawasaki T, Zochi R, Gouda M, Kuwahara Y, Takahashi K, Wada Y, Onoe H, Watanabe Y: Use of [¹⁸ F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats. EJNMMI Res 2011, 1: 25. 10.1186/2191-219X-1-25PubMedCentralCrossRefPubMed

26.

Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F: Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973, 20: 415–455. 10.1016/0022-510X(73)90175-5CrossRefPubMed

27.

Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM: Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 1990, 13: 290–296. 10.1016/0166-2236(90)90112-NCrossRefPubMed

28.

Forsback S, Niemi R, Marjamäki P, Eskola O, Bergman J, Grönroos T, Haaparanta M, Haapalinna A, Rinne J, Solin O: Uptake of 6-[¹⁸ F]fluoro-L-dopa and [¹⁸ F]CFT reflect nigral neuronal loss in a rat model of Parkinson's disease. Synapse 2004, 51: 119–127. 10.1002/syn.10293CrossRefPubMed

29.

Bergström KA, Halldin C, Hall H, Lundkvist C, Ginovart N, Swahn CG, Farde L: In vitro and in vivo characterisation of nor-beta-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain. Eur J Nucl Med 1997, 24: 596–601.CrossRefPubMed

30.

Booij J, Knol RJ, Reneman L, de Bruin K, Janssen AG, van Royen EA: Iodine-123 labelled nor-beta-CIT binds to the serotonin transporter in vivo as assessed by biodistribution studies in rats. Eur J Nucl Med 1998, 25: 1666–1669. 10.1007/s002590050346CrossRefPubMed

31.

Sun W, Sugiyama K, Fang X, Yamaguchi H, Akamine S, Magata Y, Namba H: Different striatal D2-like receptor function in an early stage after unilateral striatal lesion and medial forebrain bundle lesion in rats. Brain Res 2010, 1317: 227–235.CrossRefPubMed

32.

Weng SJ, Shiue CY, Huang WS, Cheng CY, Huang SY, Li IH, Tao CC, Chou TK, Liao MH, Chang YP, Ma KH: PET imaging of serotonin transporters with 4-[¹⁸ F]-ADAM in a Parkinsonian rat model. Cell Transplant in press

33.

Sossi V, Dinelle K, Jivan S, Fischer K, Holden JE, Doudet D: In vivo dopamine transporter imaging in a unilateral 6-hydroxydopamine rat model of Parkinson disease using ¹¹ C-methylphenidate PET. J Nucl Med 2012, 53: 813–822. 10.2967/jnumed.111.101436CrossRefPubMed

34.

Kim SR, Chen X, Oo TF, Kareva T, Yarygina O, Wang C, During M, Kholodilov N, Burke RE: Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration. Ann Neurol 2011, 70: 110–120. 10.1002/ana.22383PubMedCentralCrossRefPubMed

35.

Marti MJ, Saura J, Burke RE, Jackson-Lewis V, Jimenez A, Bonastre M, Tolosa E: Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat. Brain Res 2002, 958: 185–191. 10.1016/S0006-8993(02)03694-6CrossRefPubMed

36.

Pitkonen M, Hippeläinen E, Raki M, Andressoo J-O, Urtti A, Männistö PT, Savolainen S, Saarma M, Bergström K: Advanced brain dopamine transporter imaging in mice using small animal SPECT/CT. EJNMMI Res 2012, 2: 55. 10.1186/2191-219X-2-55PubMedCentralCrossRefPubMed

37.

Meredith GE, Kang UJ: Behavioral models of Parkinson's disease in rodents: a new look at an old problem. Mov Disord 2006, 21: 1595–1606. 10.1002/mds.21010CrossRefPubMed

38.

Cheng HC, Ulane CM, Burke RE: Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 2010, 67: 715–725. 10.1002/ana.21995PubMedCentralCrossRefPubMed

Title: High correlation between in vivo [123I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats
Authors: Susanne Bäck
Mari Raki
Raimo K Tuominen
Atso Raasmaja
Kim Bergström
Pekka T Männistö
Publication date: 01-12-2013
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2013
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/2191-219X-3-46

Keynote webinar | Spotlight on medication adherence

Springer Medicine

High correlation between in vivo [¹²³I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2013

Assessment of acquisition protocols for routine imaging of Y-90 using PET/CT

Does PRRT with standard activities of 177Lu-octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions?: insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors

Pharmacokinetics of the phosphatidylserine tracers 99mTc-lactadherin and 99mTc-annexin V in pigs

The PET-derived tumor-to-blood standard uptake ratio (SUR) is superior to tumor SUV as a surrogate parameter of the metabolic rate of FDG

Gating, enhanced gating, and beyond: information utilization strategies for motion management, applied to preclinical PET

Cortical florbetapir-PET amyloid load in prodromal Alzheimer’s disease patients