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Published in: European Journal of Nuclear Medicine and Molecular Imaging 12/2010

01-12-2010 | Original Article

Levodopa and pramipexole effects on presynaptic dopamine PET markers and estimated dopamine release

Authors: Vesna Sossi, Katherine Dinelle, Michael Schulzer, Edwin Mak, Doris J. Doudet, Raúl de la Fuente-Fernández

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 12/2010

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Abstract

Purpose

Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson’s disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [Δ(DA)].

Methods

Twenty-three unilaterally 6-OHDA lesioned rats underwent an 11C-dihydrotetrabenazine (DTBZ, VMAT2 marker), an 11C-methylphenidate (MP, DAT marker), and a double 11C-raclopride (RAC, D2-type receptor marker) scan. They were assigned to three treatment groups: saline (N = 7), pramipexole (N = 8), and levodopa (N = 8). After 4 weeks of treatment, imaging was repeated.

Results

Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on Δ(DA).

Conclusion

These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level.
Literature
1.
2.
go back to reference Parkinson’s Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287:1653–61.CrossRef Parkinson’s Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287:1653–61.CrossRef
3.
go back to reference Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61(7):1044–53.CrossRefPubMed Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61(7):1044–53.CrossRefPubMed
4.
go back to reference Ahlskog JE. Slowing Parkinson’s disease progression: recent dopamine agonist trials. Neurology 2003;60(3):381–9.PubMed Ahlskog JE. Slowing Parkinson’s disease progression: recent dopamine agonist trials. Neurology 2003;60(3):381–9.PubMed
5.
go back to reference Albin RL, Frey KA. Initial agonist treatment of Parkinson disease: a critique. Neurology 2003;60(3):390–4.PubMed Albin RL, Frey KA. Initial agonist treatment of Parkinson disease: a critique. Neurology 2003;60(3):390–4.PubMed
6.
go back to reference Guttman M, Stewart D, Hussey D, Wilson A, Houle S, Kish S. Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD. Neurology 2001;56(11):1559–64.PubMed Guttman M, Stewart D, Hussey D, Wilson A, Houle S, Kish S. Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD. Neurology 2001;56(11):1559–64.PubMed
7.
go back to reference Masuo Y, Pélaprat D, Scherman D, Rostène W. [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett 1990;114:45–50.CrossRefPubMed Masuo Y, Pélaprat D, Scherman D, Rostène W. [3H]Dihydrotetrabenazine, a new marker for the visualization of dopaminergic denervation in the rat striatum. Neurosci Lett 1990;114:45–50.CrossRefPubMed
8.
go back to reference Vander Borght TM, Sima AAF, Kilbourn MR, Desmond TJ, Kuhl DE, Frey K. [3H]methoxytetrabenazine: a high specific activity ligand for estimating monoaminergic neuronal integrity. Neuroscience 1995;68(3):955–62.CrossRefPubMed Vander Borght TM, Sima AAF, Kilbourn MR, Desmond TJ, Kuhl DE, Frey K. [3H]methoxytetrabenazine: a high specific activity ligand for estimating monoaminergic neuronal integrity. Neuroscience 1995;68(3):955–62.CrossRefPubMed
9.
go back to reference Kemmerer ES, Desmond TJ, Albin RL, Kilbourn MR, Frey KA. Treatment effects on nigrostriatal projection integrity in partial 6-OHDA lesions: comparison of L-DOPA and pramipexole. Exp Neurol 2003;183:81–6.CrossRefPubMed Kemmerer ES, Desmond TJ, Albin RL, Kilbourn MR, Frey KA. Treatment effects on nigrostriatal projection integrity in partial 6-OHDA lesions: comparison of L-DOPA and pramipexole. Exp Neurol 2003;183:81–6.CrossRefPubMed
10.
go back to reference de la Fuente-Fernández R, Furtado S, Guttman M, Furukawa Y, Lee CS, Calne DB, et al. VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET. Synapse 2003;49(1):20–8.CrossRef de la Fuente-Fernández R, Furtado S, Guttman M, Furukawa Y, Lee CS, Calne DB, et al. VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET. Synapse 2003;49(1):20–8.CrossRef
11.
go back to reference de la Fuente-Fernández R, Sossi V, McCormick S, Schulzer M, Ruth TJ, Stoessl AJ. Visualizing vesicular dopamine dynamics in Parkinson’s disease. Synapse 2009;63(8):713–6.CrossRefPubMed de la Fuente-Fernández R, Sossi V, McCormick S, Schulzer M, Ruth TJ, Stoessl AJ. Visualizing vesicular dopamine dynamics in Parkinson’s disease. Synapse 2009;63(8):713–6.CrossRefPubMed
12.
go back to reference Tong J, Wilson AA, Boileau I, Houle S, Kish SJ. Dopamine modulating drugs influence striatal (+)-[11C]DTBZ binding in rats: VMAT2 binding is sensitive to changes in vesicular dopamine concentration. Synapse 2008;62(11):873–6.CrossRefPubMed Tong J, Wilson AA, Boileau I, Houle S, Kish SJ. Dopamine modulating drugs influence striatal (+)-[11C]DTBZ binding in rats: VMAT2 binding is sensitive to changes in vesicular dopamine concentration. Synapse 2008;62(11):873–6.CrossRefPubMed
13.
go back to reference de la Fuente-Fernández R, Lu JQ, Sossi V, Jivan S, Schulzer M, Holden JE, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 2001;49(3):298–303.CrossRefPubMed de la Fuente-Fernández R, Lu JQ, Sossi V, Jivan S, Schulzer M, Holden JE, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 2001;49(3):298–303.CrossRefPubMed
14.
go back to reference Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99(2):381–92.CrossRefPubMed Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99(2):381–92.CrossRefPubMed
15.
go back to reference Pavese N, Evans AH, Tai YF, Hotton G, Brooks DJ, Lees AJ, et al. Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study. Neurology 2006;67(9):1612–7.CrossRefPubMed Pavese N, Evans AH, Tai YF, Hotton G, Brooks DJ, Lees AJ, et al. Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study. Neurology 2006;67(9):1612–7.CrossRefPubMed
16.
go back to reference Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342(20):1484–91.CrossRefPubMed Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342(20):1484–91.CrossRefPubMed
17.
go back to reference Nadjar A, Gerfen CR, Bezard E. Priming for l-dopa-induced dyskinesia in Parkinson’s disease: a feature inherent to the treatment or the disease? Prog Neurobiol 2009;87(1):1–9.CrossRefPubMed Nadjar A, Gerfen CR, Bezard E. Priming for l-dopa-induced dyskinesia in Parkinson’s disease: a feature inherent to the treatment or the disease? Prog Neurobiol 2009;87(1):1–9.CrossRefPubMed
18.
go back to reference Sossi V, Dinelle K, Topping GJ, Holden JE, Doudet D, Schulzer M, et al. Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson’s: an in vivo imaging study. J Neurochem 2009;109(1):85–92.CrossRefPubMed Sossi V, Dinelle K, Topping GJ, Holden JE, Doudet D, Schulzer M, et al. Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson’s: an in vivo imaging study. J Neurochem 2009;109(1):85–92.CrossRefPubMed
19.
go back to reference Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego: Academic; 1998. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego: Academic; 1998.
20.
go back to reference Breese GR, Traylor TD. Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine. Br J Pharmacol 1971;42:88–99.PubMed Breese GR, Traylor TD. Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine. Br J Pharmacol 1971;42:88–99.PubMed
21.
go back to reference Kelly PH, Iversen SD. Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 1976;40:45–56.CrossRefPubMed Kelly PH, Iversen SD. Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 1976;40:45–56.CrossRefPubMed
22.
go back to reference Whishaw IQ, Gorny B, Tran-Nguyen LTL, Casteñeda E, Miklyaeva EI, Pellis SM. Making two movements at once: impairments of movement, posture, and their integration underlie the adult skilled reaching deficit of neonatally dopamine-depleted rats. Behav Brain Res 1994;61:65–77.CrossRefPubMed Whishaw IQ, Gorny B, Tran-Nguyen LTL, Casteñeda E, Miklyaeva EI, Pellis SM. Making two movements at once: impairments of movement, posture, and their integration underlie the adult skilled reaching deficit of neonatally dopamine-depleted rats. Behav Brain Res 1994;61:65–77.CrossRefPubMed
23.
go back to reference Chernoloz O, El Mansari M, Blier P. Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain. Neuropsychopharmacology 2009;34(3):651–61.CrossRefPubMed Chernoloz O, El Mansari M, Blier P. Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain. Neuropsychopharmacology 2009;34(3):651–61.CrossRefPubMed
24.
go back to reference Kim JS, Lee JS, Im KC, Kim SJ, Kim SY, Lee DS, et al. Performance measurement of the microPET focus 120 scanner. J Nucl Med 2007;48:1527–35.CrossRefPubMed Kim JS, Lee JS, Im KC, Kim SJ, Kim SY, Lee DS, et al. Performance measurement of the microPET focus 120 scanner. J Nucl Med 2007;48:1527–35.CrossRefPubMed
25.
go back to reference Sossi V, Holden JE, Topping GJ, Camborde ML, Kornelsen R, McCormick S, et al. In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD. J Cereb Blood Flow Metab 2007;27(7):1407–15.CrossRefPubMed Sossi V, Holden JE, Topping GJ, Camborde ML, Kornelsen R, McCormick S, et al. In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD. J Cereb Blood Flow Metab 2007;27(7):1407–15.CrossRefPubMed
26.
go back to reference Schiffer WK, Alexoff DL, Shea C, Logan J, Dewey SL. Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging. J Neurosci Methods 2005;144(1):25–34.CrossRefPubMed Schiffer WK, Alexoff DL, Shea C, Logan J, Dewey SL. Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging. J Neurosci Methods 2005;144(1):25–34.CrossRefPubMed
27.
go back to reference Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 1997;6(4):279–87.CrossRefPubMed Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 1997;6(4):279–87.CrossRefPubMed
28.
go back to reference Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.CrossRefPubMed Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.CrossRefPubMed
29.
go back to reference Zigmond MJ, Stricker EM, Berger TW. Parkinsonism: insights from animal models utilizing neurotoxic agents. In: Coyle JY, editor. Animal models of dementia. New York: Alan R. Liss; 1987. p. 1–38. Zigmond MJ, Stricker EM, Berger TW. Parkinsonism: insights from animal models utilizing neurotoxic agents. In: Coyle JY, editor. Animal models of dementia. New York: Alan R. Liss; 1987. p. 1–38.
30.
go back to reference Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27(9):1533–9.CrossRefPubMed Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27(9):1533–9.CrossRefPubMed
31.
go back to reference Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47(4):493–503.CrossRefPubMed Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47(4):493–503.CrossRefPubMed
32.
go back to reference Truong JG, Rau KS, Hanson GR, Fleckenstein AE. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson’s neurodegeneration. Eur J Pharmacol 2003;474(2-3):223–6.CrossRefPubMed Truong JG, Rau KS, Hanson GR, Fleckenstein AE. Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson’s neurodegeneration. Eur J Pharmacol 2003;474(2-3):223–6.CrossRefPubMed
33.
go back to reference Piercey MF, Hoffmann WE, Smith MW, Hyslop DK. Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists. Eur J Pharmacol 1996;312(1):35–44.CrossRefPubMed Piercey MF, Hoffmann WE, Smith MW, Hyslop DK. Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists. Eur J Pharmacol 1996;312(1):35–44.CrossRefPubMed
34.
go back to reference Rodriguez M, Gonzalez S, Morales I, Sabate M, Gonzalez-Hernandez T, Gonzalez-Mora JL. Nigrostriatal cell firing action on the dopamine transporter. Eur J Neurosci 2007;25:2755–65.CrossRefPubMed Rodriguez M, Gonzalez S, Morales I, Sabate M, Gonzalez-Hernandez T, Gonzalez-Mora JL. Nigrostriatal cell firing action on the dopamine transporter. Eur J Neurosci 2007;25:2755–65.CrossRefPubMed
35.
go back to reference Sossi V, de la Fuente-Fernández R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol 2007;62(5):468–74.CrossRefPubMed Sossi V, de la Fuente-Fernández R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol 2007;62(5):468–74.CrossRefPubMed
36.
go back to reference Wu Q, Reith ME, Walker QD, Kuhn CM, Carroll FI, Garris PA. Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study. J Neurosci 2002;22:6272–81.PubMed Wu Q, Reith ME, Walker QD, Kuhn CM, Carroll FI, Garris PA. Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study. J Neurosci 2002;22:6272–81.PubMed
37.
go back to reference Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP. Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci 2003;18:1731–8.CrossRefPubMed Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP. Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci 2003;18:1731–8.CrossRefPubMed
38.
go back to reference de la Fuente-Fernández R, Lim AS, Sossi V, Holden JE, Caine DB, Ruth TJ, et al. Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. J Cereb Blood Flow Metab 2001;21:1151–9.CrossRef de la Fuente-Fernández R, Lim AS, Sossi V, Holden JE, Caine DB, Ruth TJ, et al. Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. J Cereb Blood Flow Metab 2001;21:1151–9.CrossRef
39.
go back to reference Bordet R, Ridray S, Carboni S, Diaz J, Sokoloff P, Schwartz JC. Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc Natl Acad Sci U S A 1997;94:3363–7.CrossRefPubMed Bordet R, Ridray S, Carboni S, Diaz J, Sokoloff P, Schwartz JC. Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc Natl Acad Sci U S A 1997;94:3363–7.CrossRefPubMed
40.
go back to reference Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006;5:25–43.CrossRefPubMed Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006;5:25–43.CrossRefPubMed
41.
go back to reference Pan T, Xie W, Jankovic J, Le W. Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection. Neurosci Lett 2005;377:106–9.CrossRefPubMed Pan T, Xie W, Jankovic J, Le W. Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection. Neurosci Lett 2005;377:106–9.CrossRefPubMed
42.
go back to reference Chiasson K, Daoust B, Levesque D, Martinoli MG. Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+ -induced toxicity in PC12 cells. Neurotox Res 2006;10:31–42.CrossRefPubMed Chiasson K, Daoust B, Levesque D, Martinoli MG. Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+ -induced toxicity in PC12 cells. Neurotox Res 2006;10:31–42.CrossRefPubMed
43.
go back to reference Lundblad M, af Bjerkén S, Cenci MA, Pomerleau F, Gerhardt GA, Strömberg I. Chronic intermittent L-DOPA treatment induces changes in dopamine release. J Neurochem 2009;108(4):998–1008.CrossRefPubMed Lundblad M, af Bjerkén S, Cenci MA, Pomerleau F, Gerhardt GA, Strömberg I. Chronic intermittent L-DOPA treatment induces changes in dopamine release. J Neurochem 2009;108(4):998–1008.CrossRefPubMed
44.
go back to reference Murer MG, Dziewczapolski G, Menalled LB, García MC, Agid Y, Gershanik O, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998;43(5):561–75.CrossRefPubMed Murer MG, Dziewczapolski G, Menalled LB, García MC, Agid Y, Gershanik O, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998;43(5):561–75.CrossRefPubMed
Metadata
Title
Levodopa and pramipexole effects on presynaptic dopamine PET markers and estimated dopamine release
Authors
Vesna Sossi
Katherine Dinelle
Michael Schulzer
Edwin Mak
Doris J. Doudet
Raúl de la Fuente-Fernández
Publication date
01-12-2010
Publisher
Springer-Verlag
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 12/2010
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-010-1581-3

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