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Effects of L-DOPA on striatal iodine-123-FP-CIT binding and behavioral parameters in the rat.

Nikolaus S, Beu M, Hautzel H, Silva AM, Antke C, Wirrwar A, Huston JP, Müller HW - Nucl Med Commun (2013)

Bottom Line: Challenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively.Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA.The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine.

View Article: PubMed Central - PubMed

Affiliation: aClinic of Nuclear Medicine, University Hospital Düsseldorf bCenter for Behavioural Neuroscience, Heinrich-Heine University, Düsseldorf cDepartment of Nuclear Medicine, Helios Clinic Krefeld GmbH, Krefeld, Germany.

ABSTRACT

Purpose: The effect of clinical L-3,4-dihydroxyphenylalanine (L-DOPA) doses on the binding of [121I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (121[I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography.

Materials and methods: DAT binding was measured at baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. For baseline and challenges, striatal equilibrium ratios (V3'') were computed as an estimation of the binding potential. Moreover, striatal V3'' values were correlated with parameters of motor and exploratory behavior.

Results: V3'' differed significantly between baseline and either dose of L-DOPA/benserazide. Moreover, V3'' differed significantly between L-DOPA treatment groups. After 5 mg/kg L-DOPA/benserazide, DAT binding was inversely correlated with sitting duration (1-5 min) and sitting frequency (10-15 min). After 10 mg/kg L-DOPA/benserazide, an inverse correlation was found between DAT binding and sitting duration (1-30 min), whereas DAT binding and duration of ambulatory activity (1-30 min) as well as head and shoulder motility (10-15 min) exhibited a positive correlation.

Conclusion: Challenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively. Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA. The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine. Moreover, there is preliminary evidence of an association between striatal DAT and motor and exploratory parameters.

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(a) Identification of the rat striatum and cerebellum relative to anatomical landmarks. The left column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]tetrofosmin scan (middle), and the superimposition of bone metabolism and perfusion scans (below). As these tracers do not pass the blood–brain barrier, their distribution allows the identification of the orbitae (1), cranium (2), and Harderian glands (3). The middle column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]HMPAO scan (middle), and the superimposition of bone metabolism and brain perfusion scans (below). The fusion of [99mTc]DPD and [99mTc]HMPAO images allows the alignment of the cranium (2) and the cerebral [99mTc]HMPAO accumulation and thus permits the identification of the cerebellum (4) relative to the rat cranium. The right column shows the rat head [99mTc]DPD scan (top), the rat head [123I]FP-CIT scan (middle), and the superimposition of [99mTc]DPD and [123I]FP-CIT images (below). The fusion image allows the identification of the rat striatum (5) relative to the orbitae (1) and the cranium (2) as visualized by [99mTc]DPD, and to the sites of extracerebral [123I]-FP-CIT accumulations corresponding to the sites of extracerebral [99mTc]tetrofosmin accumulations in the Harderian glands (3). Furthermore, the cerebellum (4) may be identified relative to the cranium (2) and to sites of cerebellar (4) HMPAO accumulations. (6) Olfactory mucous membrane. (b) Template consisting of cerebellar (4) and striatal (5) regions of interest. [123I]FP-CIT, [123I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane.
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Figure 1: (a) Identification of the rat striatum and cerebellum relative to anatomical landmarks. The left column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]tetrofosmin scan (middle), and the superimposition of bone metabolism and perfusion scans (below). As these tracers do not pass the blood–brain barrier, their distribution allows the identification of the orbitae (1), cranium (2), and Harderian glands (3). The middle column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]HMPAO scan (middle), and the superimposition of bone metabolism and brain perfusion scans (below). The fusion of [99mTc]DPD and [99mTc]HMPAO images allows the alignment of the cranium (2) and the cerebral [99mTc]HMPAO accumulation and thus permits the identification of the cerebellum (4) relative to the rat cranium. The right column shows the rat head [99mTc]DPD scan (top), the rat head [123I]FP-CIT scan (middle), and the superimposition of [99mTc]DPD and [123I]FP-CIT images (below). The fusion image allows the identification of the rat striatum (5) relative to the orbitae (1) and the cranium (2) as visualized by [99mTc]DPD, and to the sites of extracerebral [123I]-FP-CIT accumulations corresponding to the sites of extracerebral [99mTc]tetrofosmin accumulations in the Harderian glands (3). Furthermore, the cerebellum (4) may be identified relative to the cranium (2) and to sites of cerebellar (4) HMPAO accumulations. (6) Olfactory mucous membrane. (b) Template consisting of cerebellar (4) and striatal (5) regions of interest. [123I]FP-CIT, [123I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane.

Mentions: Imaging data were evaluated using the Multi-Purpose-Imaging-Tool (MPI-Tool V3.29; Advanced Tomo Vision GmbH, Kerpen, Germany) as previously described 21,22. Briefly, target and reference regions were identified using sets of fusion images ([99mTc]DPD-[99mTc]tetrofosmin, [99mTc]DPD-[99mTc]HMPAO, [99mTc]DPD-[123I]IFP-CIT), allowing the identification of extracerebral anatomical landmarks such as cranium, orbitae, and Harderian glands and the localization of the respective regions relative to the sites of specific accumulation of metabolic and perfusion markers (Fig. 1a). On coronal slices, striatal target and cerebellar reference regions were defined using the regional activity maxima (Fig. 1b). Thereby, maximum striatal count rates (counts/pixel) were determined on coronal slices by defining a circular region covering an area of 1.5 mm2, which comprised a total of 11 pixels. On the same slices used for the determination of maximum striatal count rates, reference count rates (counts/pixel) were obtained in an elliptic region (area, 7 mm2 comprising a total of 53 pixels) ∼15 mm posterior to the frontal cortex corresponding anatomically to the rat cerebellum. A template of striatal and cerebellar regions was positioned on the individual images by visual inspection without changing their shape or size. Left and right striatal radioactivity concentrations were averaged. For baseline and treatment conditions, the equilibrium ratio of the distribution volumes of the specifically and the nonspecifically bound compartment [V3′′=VT (striatum)/VT (cerebellum)−1] was computed as an estimate for the binding potential 27.


Effects of L-DOPA on striatal iodine-123-FP-CIT binding and behavioral parameters in the rat.

Nikolaus S, Beu M, Hautzel H, Silva AM, Antke C, Wirrwar A, Huston JP, Müller HW - Nucl Med Commun (2013)

(a) Identification of the rat striatum and cerebellum relative to anatomical landmarks. The left column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]tetrofosmin scan (middle), and the superimposition of bone metabolism and perfusion scans (below). As these tracers do not pass the blood–brain barrier, their distribution allows the identification of the orbitae (1), cranium (2), and Harderian glands (3). The middle column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]HMPAO scan (middle), and the superimposition of bone metabolism and brain perfusion scans (below). The fusion of [99mTc]DPD and [99mTc]HMPAO images allows the alignment of the cranium (2) and the cerebral [99mTc]HMPAO accumulation and thus permits the identification of the cerebellum (4) relative to the rat cranium. The right column shows the rat head [99mTc]DPD scan (top), the rat head [123I]FP-CIT scan (middle), and the superimposition of [99mTc]DPD and [123I]FP-CIT images (below). The fusion image allows the identification of the rat striatum (5) relative to the orbitae (1) and the cranium (2) as visualized by [99mTc]DPD, and to the sites of extracerebral [123I]-FP-CIT accumulations corresponding to the sites of extracerebral [99mTc]tetrofosmin accumulations in the Harderian glands (3). Furthermore, the cerebellum (4) may be identified relative to the cranium (2) and to sites of cerebellar (4) HMPAO accumulations. (6) Olfactory mucous membrane. (b) Template consisting of cerebellar (4) and striatal (5) regions of interest. [123I]FP-CIT, [123I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane.
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Related In: Results  -  Collection

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Figure 1: (a) Identification of the rat striatum and cerebellum relative to anatomical landmarks. The left column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]tetrofosmin scan (middle), and the superimposition of bone metabolism and perfusion scans (below). As these tracers do not pass the blood–brain barrier, their distribution allows the identification of the orbitae (1), cranium (2), and Harderian glands (3). The middle column shows the rat head [99mTc]DPD scan (top), the rat head [99mTc]HMPAO scan (middle), and the superimposition of bone metabolism and brain perfusion scans (below). The fusion of [99mTc]DPD and [99mTc]HMPAO images allows the alignment of the cranium (2) and the cerebral [99mTc]HMPAO accumulation and thus permits the identification of the cerebellum (4) relative to the rat cranium. The right column shows the rat head [99mTc]DPD scan (top), the rat head [123I]FP-CIT scan (middle), and the superimposition of [99mTc]DPD and [123I]FP-CIT images (below). The fusion image allows the identification of the rat striatum (5) relative to the orbitae (1) and the cranium (2) as visualized by [99mTc]DPD, and to the sites of extracerebral [123I]-FP-CIT accumulations corresponding to the sites of extracerebral [99mTc]tetrofosmin accumulations in the Harderian glands (3). Furthermore, the cerebellum (4) may be identified relative to the cranium (2) and to sites of cerebellar (4) HMPAO accumulations. (6) Olfactory mucous membrane. (b) Template consisting of cerebellar (4) and striatal (5) regions of interest. [123I]FP-CIT, [123I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane.
Mentions: Imaging data were evaluated using the Multi-Purpose-Imaging-Tool (MPI-Tool V3.29; Advanced Tomo Vision GmbH, Kerpen, Germany) as previously described 21,22. Briefly, target and reference regions were identified using sets of fusion images ([99mTc]DPD-[99mTc]tetrofosmin, [99mTc]DPD-[99mTc]HMPAO, [99mTc]DPD-[123I]IFP-CIT), allowing the identification of extracerebral anatomical landmarks such as cranium, orbitae, and Harderian glands and the localization of the respective regions relative to the sites of specific accumulation of metabolic and perfusion markers (Fig. 1a). On coronal slices, striatal target and cerebellar reference regions were defined using the regional activity maxima (Fig. 1b). Thereby, maximum striatal count rates (counts/pixel) were determined on coronal slices by defining a circular region covering an area of 1.5 mm2, which comprised a total of 11 pixels. On the same slices used for the determination of maximum striatal count rates, reference count rates (counts/pixel) were obtained in an elliptic region (area, 7 mm2 comprising a total of 53 pixels) ∼15 mm posterior to the frontal cortex corresponding anatomically to the rat cerebellum. A template of striatal and cerebellar regions was positioned on the individual images by visual inspection without changing their shape or size. Left and right striatal radioactivity concentrations were averaged. For baseline and treatment conditions, the equilibrium ratio of the distribution volumes of the specifically and the nonspecifically bound compartment [V3′′=VT (striatum)/VT (cerebellum)−1] was computed as an estimate for the binding potential 27.

Bottom Line: Challenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively.Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA.The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine.

View Article: PubMed Central - PubMed

Affiliation: aClinic of Nuclear Medicine, University Hospital Düsseldorf bCenter for Behavioural Neuroscience, Heinrich-Heine University, Düsseldorf cDepartment of Nuclear Medicine, Helios Clinic Krefeld GmbH, Krefeld, Germany.

ABSTRACT

Purpose: The effect of clinical L-3,4-dihydroxyphenylalanine (L-DOPA) doses on the binding of [121I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (121[I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography.

Materials and methods: DAT binding was measured at baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. For baseline and challenges, striatal equilibrium ratios (V3'') were computed as an estimation of the binding potential. Moreover, striatal V3'' values were correlated with parameters of motor and exploratory behavior.

Results: V3'' differed significantly between baseline and either dose of L-DOPA/benserazide. Moreover, V3'' differed significantly between L-DOPA treatment groups. After 5 mg/kg L-DOPA/benserazide, DAT binding was inversely correlated with sitting duration (1-5 min) and sitting frequency (10-15 min). After 10 mg/kg L-DOPA/benserazide, an inverse correlation was found between DAT binding and sitting duration (1-30 min), whereas DAT binding and duration of ambulatory activity (1-30 min) as well as head and shoulder motility (10-15 min) exhibited a positive correlation.

Conclusion: Challenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively. Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA. The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine. Moreover, there is preliminary evidence of an association between striatal DAT and motor and exploratory parameters.

Show MeSH