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Published in: Molecular Imaging and Biology 5/2006

01-09-2006 | Research Article

Evaluation of the Integrity of the Dopamine System in a Rodent Model of Parkinson’s Disease: Small Animal Positron Emission Tomography Compared to Behavioral Assessment and Autoradiography

Authors: Elissa M. Strome, Ivan L. Cepeda, Vesna Sossi, Doris J. Doudet

Published in: Molecular Imaging and Biology | Issue 5/2006

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Abstract

Purpose

In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), it is important to determine lesion severity. This evaluation can be performed in vivo, through evaluation of dopamine (DA)-dependent motor function or with small animal positron emission tomography (microPET), or at postmortem, by examining markers for DA neurons.

Procedures

Rats were given mild or severe unilateral 6-OHDA lesions, scanned with the tracer [11C](±)dihydrotetrabenazine ([11C]DTBZ), and tested on a tapered/ledged beam-walking task. At postmortem, autoradiography was performed with [11C]DTBZ.

Results

Autoradiography was significantly correlated with microPET and behavioral scores, whereas the microPET and behavioral data were not significantly correlated.

Conclusions

This study shows that behavioral analysis, microPET, and autoradiography are all good tools for measuring the integrity of the DA system, and demonstrates the utility of the tapered/ledged beam-walking test to screen for lesion severity, as well as the importance of including postmortem analysis after in vivo imaging studies.
Literature
1.
go back to reference Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110PubMedCrossRef Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110PubMedCrossRef
2.
go back to reference Costall B, Naylor RJ, Pycock C (1976) Non-specific supersensitivity of striatal dopamine receptors after 6-hydroxydopamine lesion of the nigrostriatal pathway. Eur J Pharmacol 35:276–283PubMed Costall B, Naylor RJ, Pycock C (1976) Non-specific supersensitivity of striatal dopamine receptors after 6-hydroxydopamine lesion of the nigrostriatal pathway. Eur J Pharmacol 35:276–283PubMed
3.
go back to reference Morelli M, Fenu S, Garau L, Di Chiara G (1989) Time and dose dependence of the ‘priming’ of the expression of dopamine receptor supersensitivity. Eur J Pharmacol 162:329–335PubMedCrossRef Morelli M, Fenu S, Garau L, Di Chiara G (1989) Time and dose dependence of the ‘priming’ of the expression of dopamine receptor supersensitivity. Eur J Pharmacol 162:329–335PubMedCrossRef
4.
go back to reference Klug JM, Norman AB (1993) Long-term sensitization of apomorphine-induced rotation behavior in rats with dopamine deafferentation or excitotoxin lesions of the striatum. Pharmacol Biochem Behav 46:397–403PubMedCrossRef Klug JM, Norman AB (1993) Long-term sensitization of apomorphine-induced rotation behavior in rats with dopamine deafferentation or excitotoxin lesions of the striatum. Pharmacol Biochem Behav 46:397–403PubMedCrossRef
5.
go back to reference Tai YC, Ruangma A, Rowland D, et al. (2005) Performance evaluation of the microPET focus: A third-generation microPET scanner dedicated to animal imaging. J Nucl Med 46:455–463PubMed Tai YC, Ruangma A, Rowland D, et al. (2005) Performance evaluation of the microPET focus: A third-generation microPET scanner dedicated to animal imaging. J Nucl Med 46:455–463PubMed
6.
go back to reference Yang Y, Tai YC, Siegel S, et al. (2004) Optimization and performance evaluation of the microPET II scanner for in vivo small-animal imaging. Phys Med Biol 49:2527–2545PubMedCrossRef Yang Y, Tai YC, Siegel S, et al. (2004) Optimization and performance evaluation of the microPET II scanner for in vivo small-animal imaging. Phys Med Biol 49:2527–2545PubMedCrossRef
7.
go back to reference Knoess C, Siegel S, Smith A, et al. (2003) Performance evaluation of the microPET R4 PET scanner for rodents. Eur J Nucl Med Mol Imaging 30:737–747PubMedCrossRef Knoess C, Siegel S, Smith A, et al. (2003) Performance evaluation of the microPET R4 PET scanner for rodents. Eur J Nucl Med Mol Imaging 30:737–747PubMedCrossRef
8.
go back to reference Tai C, Chatziioannou A, Siegel S, et al. (2001) Performance evaluation of the microPET P4: A PET system dedicated to animal imaging. Phys Med Biol 46:1845–1862PubMedCrossRef Tai C, Chatziioannou A, Siegel S, et al. (2001) Performance evaluation of the microPET P4: A PET system dedicated to animal imaging. Phys Med Biol 46:1845–1862PubMedCrossRef
9.
go back to reference Tai YC, Chatziioannou AF, Yang Y, et al. (2003) MicroPET II: design, development and initial performance of an improved microPET scanner for small-animal imaging. Phys Med Biol 48:1519–1537PubMedCrossRef Tai YC, Chatziioannou AF, Yang Y, et al. (2003) MicroPET II: design, development and initial performance of an improved microPET scanner for small-animal imaging. Phys Med Biol 48:1519–1537PubMedCrossRef
10.
go back to reference Huang N, Ase AR, Hebert C, van Gelder NM, Reader TA (1997) Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: Homogenate binding and autoradiographic studies. Neurochem Int 30:277–290PubMedCrossRef Huang N, Ase AR, Hebert C, van Gelder NM, Reader TA (1997) Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: Homogenate binding and autoradiographic studies. Neurochem Int 30:277–290PubMedCrossRef
11.
go back to reference Rinne JO, Laihinen A, Ruottinen H, et al. (1995) Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: A PET study with [11C]raclopride. J Neurol Sci 132:156–161PubMedCrossRef Rinne JO, Laihinen A, Ruottinen H, et al. (1995) Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: A PET study with [11C]raclopride. J Neurol Sci 132:156–161PubMedCrossRef
12.
go back to reference Narang N, Wamsley JK (1995) Time dependent changes in DA uptake sites, D1 and D2 receptor binding and mRNA after 6-OHDA lesions of the medial forebrain bundle in the rat brain. J Chem Neuroanat 9:41–53PubMedCrossRef Narang N, Wamsley JK (1995) Time dependent changes in DA uptake sites, D1 and D2 receptor binding and mRNA after 6-OHDA lesions of the medial forebrain bundle in the rat brain. J Chem Neuroanat 9:41–53PubMedCrossRef
13.
go back to reference Nikolaus S, Larisch R, Beu M, Vosberg H, Muller-Gartner HW (2001) Imaging of striatal dopamine D2 receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: A validation study with 18F-(N-Methyl)Benperidol. J Nucl Med 42:1691–1696PubMed Nikolaus S, Larisch R, Beu M, Vosberg H, Muller-Gartner HW (2001) Imaging of striatal dopamine D2 receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: A validation study with 18F-(N-Methyl)Benperidol. J Nucl Med 42:1691–1696PubMed
14.
go back to reference Doudet DJ, Jivan S, Ruth TJ, Holden JE (2002) Density and affinity of the dopamine D2 receptors in aged symptomatic and asymptomatic MPTP-treated monkeys: PET studies with [11C]raclopride. Synapse 44:198–202PubMedCrossRef Doudet DJ, Jivan S, Ruth TJ, Holden JE (2002) Density and affinity of the dopamine D2 receptors in aged symptomatic and asymptomatic MPTP-treated monkeys: PET studies with [11C]raclopride. Synapse 44:198–202PubMedCrossRef
15.
go back to reference Wilson JM, Nobrega JN, Carroll ME, et al. (1994) Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. J Neurosci 14:2966–2979PubMed Wilson JM, Nobrega JN, Carroll ME, et al. (1994) Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. J Neurosci 14:2966–2979PubMed
16.
go back to reference Kilbourn MR, Sherman PS, Pisani T (1992) Repeated reserpine administration reduces in vivo [18F]GBR 13119 binding to the dopamine uptake site. Eur J Pharmacol 216:109–112PubMedCrossRef Kilbourn MR, Sherman PS, Pisani T (1992) Repeated reserpine administration reduces in vivo [18F]GBR 13119 binding to the dopamine uptake site. Eur J Pharmacol 216:109–112PubMedCrossRef
17.
go back to reference Doudet DJ (2001) PET studies in the MPTP model of Parkinson's disease. Adv Neurol 86:187–195PubMed Doudet DJ (2001) PET studies in the MPTP model of Parkinson's disease. Adv Neurol 86:187–195PubMed
18.
go back to reference Lee CS, Samii A, Sossi V, et al. (2000) In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol 47:493–503PubMedCrossRef Lee CS, Samii A, Sossi V, et al. (2000) In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol 47:493–503PubMedCrossRef
19.
go back to reference Wilson JM, Kish SJ (1996) The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J Neurosci 16:3507–3510PubMed Wilson JM, Kish SJ (1996) The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J Neurosci 16:3507–3510PubMed
20.
go back to reference Vander Borght T, Kilbourn M, Desmond T, Kuhl D, Frey K (1995) The vesicular monoamine transporter is not regulated by dopaminergic treatments. Eur J Pharmacol 294:577–583CrossRef Vander Borght T, Kilbourn M, Desmond T, Kuhl D, Frey K (1995) The vesicular monoamine transporter is not regulated by dopaminergic treatments. Eur J Pharmacol 294:577–583CrossRef
21.
go back to reference Frey KA, Wieland DM, Kilbourn MR (1998) Imaging of monoaminergic and cholinergic vesicular transporters in the brain. Adv Pharmacol 42:269–272PubMedCrossRef Frey KA, Wieland DM, Kilbourn MR (1998) Imaging of monoaminergic and cholinergic vesicular transporters in the brain. Adv Pharmacol 42:269–272PubMedCrossRef
22.
go back to reference Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. San Diego: Academic Press Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. San Diego: Academic Press
23.
go back to reference Schallert T, Woodlee MT (2005) Orienting and Placing. In: Whishaw IQ, Kolb B (eds) The Behavior of the Laboratory Rat: A Handbook with Tests. New York: Oxford University Press, pp 129–140 Schallert T, Woodlee MT (2005) Orienting and Placing. In: Whishaw IQ, Kolb B (eds) The Behavior of the Laboratory Rat: A Handbook with Tests. New York: Oxford University Press, pp 129–140
24.
go back to reference Zhao CS, Puurunen K, Schallert T, Sivenius J, Jolkkonen J (2005) Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav Brain Res 158:211–220PubMedCrossRef Zhao CS, Puurunen K, Schallert T, Sivenius J, Jolkkonen J (2005) Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav Brain Res 158:211–220PubMedCrossRef
25.
go back to reference Feeney DM, Gonzalez A, Law WA (1982) Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 217:855–857PubMedCrossRef Feeney DM, Gonzalez A, Law WA (1982) Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 217:855–857PubMedCrossRef
26.
go back to reference Walsh SL, Wagner GC (1992) Motor impairments after methamphetamine-induced neurotoxicity in the rat. J Pharmacol Exp Ther 263:617–626PubMed Walsh SL, Wagner GC (1992) Motor impairments after methamphetamine-induced neurotoxicity in the rat. J Pharmacol Exp Ther 263:617–626PubMed
27.
go back to reference Bowenkamp KE, Ujhelyi L, Cline EJ, Bickford PC (2000) Effects of intra-striatal GDNF on motor coordination and striatal electrophysiology in aged F344 rats. Neurobiol Aging 21:117–124PubMedCrossRef Bowenkamp KE, Ujhelyi L, Cline EJ, Bickford PC (2000) Effects of intra-striatal GDNF on motor coordination and striatal electrophysiology in aged F344 rats. Neurobiol Aging 21:117–124PubMedCrossRef
28.
go back to reference Zar JH (1999) Biostatistical Analysis. Upper Saddle River: Prentice-Hall Zar JH (1999) Biostatistical Analysis. Upper Saddle River: Prentice-Hall
29.
go back to reference Rubins DJ, Meadors AK, Yee S, Melega WP, Cherry SR (2001) Evaluation of a stereotactic frame for repositioning of the rat brain in serial positron emission tomography imaging studies. J Neurosci Methods 107:63–70PubMedCrossRef Rubins DJ, Meadors AK, Yee S, Melega WP, Cherry SR (2001) Evaluation of a stereotactic frame for repositioning of the rat brain in serial positron emission tomography imaging studies. J Neurosci Methods 107:63–70PubMedCrossRef
30.
go back to reference Jewett DM, Kilbourn MR, Lee LC (1997) A simple synthesis of [11C]dihydrotetrabenazine (DTBZ). Nucl Med Biol 24:197–199PubMedCrossRef Jewett DM, Kilbourn MR, Lee LC (1997) A simple synthesis of [11C]dihydrotetrabenazine (DTBZ). Nucl Med Biol 24:197–199PubMedCrossRef
31.
go back to reference Alexoff D, Vaska P, Marsteller D, et al. (2003) Reproducibility of 11C-raclopride binding in the rat brain measured with microPET R4: effects of scatter correction and tracer specific activity. J Nucl Med 44:815–822PubMed Alexoff D, Vaska P, Marsteller D, et al. (2003) Reproducibility of 11C-raclopride binding in the rat brain measured with microPET R4: effects of scatter correction and tracer specific activity. J Nucl Med 44:815–822PubMed
32.
go back to reference Strome EM, Jivan S, Doudet DJ (2005) Quantitative in vitro phosphor imaging using [3H] and [18F] radioligands: The effects of chronic desipramine treatment on serotonin 5-HT2 receptors. J Neurosci Methods 141:143–154PubMedCrossRef Strome EM, Jivan S, Doudet DJ (2005) Quantitative in vitro phosphor imaging using [3H] and [18F] radioligands: The effects of chronic desipramine treatment on serotonin 5-HT2 receptors. J Neurosci Methods 141:143–154PubMedCrossRef
33.
go back to reference Darchen F, Masuo Y, Vial M, Rostene W, Scherman D (1989) Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin. Neuroscience 33:341–349PubMedCrossRef Darchen F, Masuo Y, Vial M, Rostene W, Scherman D (1989) Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin. Neuroscience 33:341–349PubMedCrossRef
34.
go back to reference Masuo Y, Pelaprat D, Scherman D, Rostene W (1990) [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett 114:45–50PubMedCrossRef Masuo Y, Pelaprat D, Scherman D, Rostene W (1990) [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett 114:45–50PubMedCrossRef
35.
go back to reference Nikolaus S, Larisch R, Beu M, et al. (2003) In vivo measurement of D2 receptor density and affinity for 18F-(3-N-methyl) benperidol in the rat striatum with a PET system for small laboratory animals. J Nucl Med 44:618–624PubMed Nikolaus S, Larisch R, Beu M, et al. (2003) In vivo measurement of D2 receptor density and affinity for 18F-(3-N-methyl) benperidol in the rat striatum with a PET system for small laboratory animals. J Nucl Med 44:618–624PubMed
36.
go back to reference Matsumura A, Mizokawa S, Tanaka M, et al. (2003) Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: Comparison between quantitative data obtained with microPET and ex vivo autoradiography. Neuroimage 20:2040–2050PubMedCrossRef Matsumura A, Mizokawa S, Tanaka M, et al. (2003) Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: Comparison between quantitative data obtained with microPET and ex vivo autoradiography. Neuroimage 20:2040–2050PubMedCrossRef
37.
go back to reference Moore AH, Osteen CL, Chatziioannou A, Hovda DA, Cherry SR (2000) Quantitative assessment of longitudinal metabolic changes in vivo after traumatic brain injury in the adult rat using FDG-microPET. J Cereb Blood Flow Metab 20:1492–1501PubMedCrossRef Moore AH, Osteen CL, Chatziioannou A, Hovda DA, Cherry SR (2000) Quantitative assessment of longitudinal metabolic changes in vivo after traumatic brain injury in the adult rat using FDG-microPET. J Cereb Blood Flow Metab 20:1492–1501PubMedCrossRef
38.
go back to reference Momosaki S, Hatano K, Kawasumi Y, et al. (2004) Rat-PET study without anesthesia: Anesthetics modify the dopamine D1 receptor binding in rat brain. Synapse 54:207–213PubMedCrossRef Momosaki S, Hatano K, Kawasumi Y, et al. (2004) Rat-PET study without anesthesia: Anesthetics modify the dopamine D1 receptor binding in rat brain. Synapse 54:207–213PubMedCrossRef
39.
go back to reference Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL (2000) Effects of (S)-ketamine on striatal dopamine: A [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 34:35–43PubMedCrossRef Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL (2000) Effects of (S)-ketamine on striatal dopamine: A [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 34:35–43PubMedCrossRef
40.
go back to reference Kobayashi K, Inoue O, Watanabe Y, Onoe H, Langstrom B (1995) Difference in response of D2 receptor binding between 11C-N-methylspiperone and 11C-raclopride against anesthetics in rhesus monkey brain. J Neural Transm Gen Sect 100:147–151PubMedCrossRef Kobayashi K, Inoue O, Watanabe Y, Onoe H, Langstrom B (1995) Difference in response of D2 receptor binding between 11C-N-methylspiperone and 11C-raclopride against anesthetics in rhesus monkey brain. J Neural Transm Gen Sect 100:147–151PubMedCrossRef
41.
go back to reference Mazziotta JC, Phelps ME, Plummer D, Kuhl DE (1981) Quantitation in positron emission computed tomography: 5. Physical–anatomical effects. J Comput Assist Tomogr 5:734–743PubMedCrossRef Mazziotta JC, Phelps ME, Plummer D, Kuhl DE (1981) Quantitation in positron emission computed tomography: 5. Physical–anatomical effects. J Comput Assist Tomogr 5:734–743PubMedCrossRef
42.
go back to reference Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787PubMedCrossRef Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787PubMedCrossRef
Metadata
Title
Evaluation of the Integrity of the Dopamine System in a Rodent Model of Parkinson’s Disease: Small Animal Positron Emission Tomography Compared to Behavioral Assessment and Autoradiography
Authors
Elissa M. Strome
Ivan L. Cepeda
Vesna Sossi
Doris J. Doudet
Publication date
01-09-2006
Publisher
Springer-Verlag
Published in
Molecular Imaging and Biology / Issue 5/2006
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-006-0051-6

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