Publications by authors named "Markus Beu"

25 Publications

  • Page 1 of 1

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

Rev Neurosci 2020 Aug;31(6):569-588

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.
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http://dx.doi.org/10.1515/revneuro-2019-0112DOI Listing
August 2020

Differential effects of D-cycloserine and amantadine on motor behavior and D receptor binding in the nigrostriatal and mesolimbic system of the adult rat.

Sci Rep 2019 11 6;9(1):16128. Epub 2019 Nov 6.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, D-40225, Düsseldorf, Germany.

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine DR binding in the brain of adult rats in relation to motor behavior. DR binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased DR binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased DR binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of DR binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of DR binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.
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http://dx.doi.org/10.1038/s41598-019-52185-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834679PMC
November 2019

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity.

Pharmacol Biochem Behav 2019 04 11;179:156-170. Epub 2019 Jan 11.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Purpose: The present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine DR binding in relation to motor and exploratory activity in the rat.

Methods: DR binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region.

Results: 40 mg/kg AMA reduced DR binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased DR binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge.

Conclusions: Results showed reductions of DR binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.
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http://dx.doi.org/10.1016/j.pbb.2018.12.010DOI Listing
April 2019

GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain.

Front Behav Neurosci 2018 14;12:38. Epub 2018 Mar 14.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

The present study assessed the effects of the GABA receptor (R) agonist muscimol (MUS), and the GABAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine DRs in relation to motor and exploratory behaviors in the rat. DR binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region. After MUS, DR binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ ≤ 0.012). In all these areas, except for the thalamus, DR binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, DR binding was significantly elevated in caudateputamen ( = 0.022) and thalamus ( = 0.047) relative to baseline. DR binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time. Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.
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http://dx.doi.org/10.3389/fnbeh.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862131PMC
March 2018

GABAergic control of neostriatal dopamine D receptor binding and behaviors in the rat.

Pharmacol Biochem Behav 2017 02 21;153:76-87. Epub 2016 Dec 21.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Purpose: The present study assessed the influence of the GABA receptor agonist muscimol and the GABA receptor antagonist bicuculline on neostriatal dopamine D receptor binding in relation to motor and exploratory behaviors in the rat.

Methods: D receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30min in an open field prior to administration of [I]S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([I]IBZM). For baseline and challenges, striatal equilibrium ratios (V″) were computed as estimation of the binding potential.

Results: Muscimol but not bicuculline reduced D receptor binding relative to baseline and to saline. Travelled distance, duration of rearing and frequency of rearing and of head-shoulder motility were lower after muscimol compared to saline. In contrast, duration of rearing and grooming and frequency of rearing, head-shoulder motility and grooming were elevated after bicuculline relative to saline. Moreover, bicuculline decreased duration of sitting and head-shoulder motility.

Conclusions: The muscimol-induced decrease of motor/exploratory behaviors can be related to an elevation of striatal dopamine levels. In contrast, bicuculline is likely to elicit a decline of synaptic dopamine, which, however, is compensated by the time of D receptor imaging studies. The results indicate direct GABAergic control over D receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.
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http://dx.doi.org/10.1016/j.pbb.2016.12.012DOI Listing
February 2017

DAT versus D2 receptor binding in the rat striatum: l-DOPA-induced motor activity is better predicted by reuptake than release of dopamine.

Synapse 2016 09 30;70(9):369-77. Epub 2016 May 30.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, D-40225, Germany.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/syn.21911DOI Listing
September 2016

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

Front Behav Neurosci 2016 22;10:80. Epub 2016 Apr 22.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor.

Methods: Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand.

Results: (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs.

Conclusions:

The Results: (a) demonstrate a direct central action of intranasally applied DA on the DAT in the dorsal striatum, indicating enhanced DA availability; and (b) provide first evidence of a Pavlovian conditioned DA response at the DAT. The latter results have relevance to understanding neurochemical mechanisms that underlie placebo action in the treatment of Parkinsonian patients.
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http://dx.doi.org/10.3389/fnbeh.2016.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840254PMC
May 2016

Corrigendum: Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2016 15;10:36. Epub 2016 Mar 15.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

[This corrects the article on p. 352 in vol. 9, PMID: 26778989.].
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http://dx.doi.org/10.3389/fnbeh.2016.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791392PMC
March 2016

FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow-Up Study.

Neurodegener Dis 2016 16;16(5-6):342-7. Epub 2016 Mar 16.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Objective: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS).

Background: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available.

Methods: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19).

Results: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences.

Conclusion: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding.
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http://dx.doi.org/10.1159/000443667DOI Listing
September 2017

Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2015 6;9:352. Epub 2016 Jan 6.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) D2 receptor binding in relation to motor and exploratory behaviors in the rat.

Methods: D2 receptor binding was measured in 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. Additional rats received injections of saline. For baseline and challenges, striatal equilibrium ratios (V[Formula: see text]) were computed as estimation of the binding potential. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [(123)I]IBZM. D2 receptor binding was measured with small animal SPECT 2 h after radioligand administration for 60 min.

Results: Both L-DOPA doses significantly reduced D2 receptor binding relative to baseline and led to significantly less ambulation, less head-shoulder motility, and more sitting relative to saline. Moreover, 10 mg/kg L-DOPA induced less head-shoulder motility, more sitting, and more grooming than 5 mg/kg L-DOPA. Analysis of time-behavior curves showed that L-DOPA-treated animals relative to saline exhibited a faster rate of decrease of ambulation frequency and a slower rate of decrease of both duration and frequency of head-shoulder motility from a lower maximum level.

Conclusions: The reductions of striatal D2 receptor binding after L-DOPA may be conceived to reflect elevated concentrations of synaptic DA. L-DOPA-treated animals showed less ambulation and less head-shoulder motility than saline-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster rate of decrease of ambulation frequency and the lower maximum levels of both head-shoulder motility duration and frequency may be interpreted in terms of influence of increased DA availability on behavioral habituation to a novel environment.
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http://dx.doi.org/10.3389/fnbeh.2015.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701934PMC
January 2016

Relationship between L-DOPA-induced reduction in motor and exploratory activity and degree of DAT binding in the rat.

Front Behav Neurosci 2014 17;8:431. Epub 2014 Dec 17.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) transporter (DAT) binding in relation to motor and exploratory behaviors in the rat.

Methods: Rats received injections of 5 mg/kg L-DOPA, 10 mg/kg L-DOPA or vehicle. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. Dopamine transporter binding was measured with small animal single-photon emission computed tomography (SPECT) 2 h after radioligand administration for 60 min.

Results: Both L-DOPA doses significantly reduced DAT binding and led to significantly less head-shoulder motility and more sitting relative to vehicle. Moreover, 10 mg/kg L-DOPA induced less distance traveled and ambulation than 5 mg/kg L-DOPA. Analysis of time-behavior (t-b) curves showed that L-DOPA-treated animals relative to vehicle exhibited (1) a faster rate of increase in duration of sitting; (2) a slower rate of increase in duration of head-shoulder motility; and (3) a slower rate of decrease in frequency of head-shoulder motility.

Conclusions: The reductions of striatal DAT binding after L-DOPA challenges reflected elevated concentrations of synaptic DA. L-DOPA-treated animals showed less head-shoulder motility and more sitting than vehicle-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster increase of sitting duration to a higher final level and the slower increase of head-shoulder motility to a lower final level relative to controls may be interpreted in terms on behavioral habituation to a novel environment.
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http://dx.doi.org/10.3389/fnbeh.2014.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269131PMC
January 2015

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

Nucl Med Commun 2013 Dec;34(12):1223-32

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.

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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http://dx.doi.org/10.1097/MNM.0b013e3283657404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815148PMC
December 2013

Pharmacological challenge and synaptic response - assessing dopaminergic function in the rat striatum with small animal single-photon emission computed tomography (SPECT) and positron emission tomography (PET).

Rev Neurosci 2011 22;22(6):625-45. Epub 2011 Nov 22.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.

Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.
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http://dx.doi.org/10.1515/RNS.2011.054DOI Listing
March 2012

Diagnostic accuracy of combined FP-CIT, IBZM, and MIBG scintigraphy in the differential diagnosis of degenerative parkinsonism: a multidimensional statistical approach.

J Nucl Med 2011 May 15;52(5):733-40. Epub 2011 Apr 15.

Department of Neurology, Faculty of Medicine and University Clinic, Heinrich Heine University, Düsseldorf, Germany.

Unlabelled: In vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is used to distinguish idiopathic Parkinson disease (PD) from atypical parkinsonian disorder (APD). However, the diagnostic accuracy of these imaging approaches as stand-alone procedures is often unsatisfying. The aim of this study was therefore to evaluate to which extent diagnostic accuracy can be increased by their combined use together with a multidimensional statistical algorithm.

Methods: The SPECT radiotracers (123)I-(S)-2-hydroxy-3-iodo-6-methoxy-N-[1-ethyl-2-pyrrodinyl)-methyl]benzamide (IBZM), (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan (FP-CIT), and meta-(123)I-iodobenzylguanidine (MIBG) were used to assess striatal postsynaptic D(2) receptor binding, striatal presynaptic dopamine transporter binding, and myocardial adrenergic innervation, respectively. Thirty-one PD and 17 APD patients were prospectively investigated. PD and APD diagnoses were established using consensus criteria and reevaluated after 37.4 ± 12.4 and 26 ± 11.6 mo in PD and APD, respectively. Test accuracy (TA) for PD-APD differentiation was computed for all logical (Boolean) combinations of imaging modalities by receiver-operating-characteristic analysis--that is, after multidimensional optimization of cutoff values.

Results: Analysis showed moderate TA for PD-APD differentiation using each molecular approach alone (IBZM, 79%; MIBG, 73%; and FP-CIT, 73%). For combined use, the highest TA resulted under the assumption that at least 2 of the 3 biologic markers had to be positive for APD using the following cutoff values: 1.46 or less for IBZM, less than 2.10 for FP-CIT, and greater than 1.43 for MIBG. This algorithm distinguished APD from PD with a sensitivity of 94%, specificity of 94% (TA, 94%), positive predictive value of 89%, and negative predictive value of 97%.

Conclusion: Results suggest that the multidimensional combination of FP-CIT, IBZM, and MIBG scintigraphy is likely to significantly increase TA in differentiating PD from APD. The differential diagnosis of degenerative parkinsonism may thus be facilitated.
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http://dx.doi.org/10.2967/jnumed.110.086959DOI Listing
May 2011

Binding of [123I]iodobenzamide to the rat D2 receptor after challenge with various doses of methylphenidate: an in vivo imaging study with dedicated small animal SPECT.

Eur J Nucl Med Mol Imaging 2011 Apr 26;38(4):694-701. Epub 2010 Nov 26.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

Purpose: The effect of various doses of methylphenidate on the binding of [(123)I]iodobenzamide ([(123)I]IBZM) to the rat D(2) receptor was assessed using small animal SPECT.

Methods: D(2) receptor binding was measured at baseline and after pretreatment with various doses of methylphenidate. For baseline and methylphenidate challenge, striatal equilibrium ratios (V(3)″) were computed as an estimation of the binding potential.

Results: After methylphenidate, striatal V(3)″ was 1.61 ± 0.61 (mean ± SD; 0.3 mg/kg), 0.91 ± 0.44 (3 mg/kg), 1.01 ± 0.44 (10 mg/kg), 0.91 ± 0.34 (30 mg/kg) and 0.99 ± 0.51 (60 mg/kg). Baseline values amounted to 1.73 ± 0.48, 1.32 ± 0.35, 1.50 ± 0.27, 1.82 ± 0.55 and 1.66 ± 0.41, respectively. Differences between baseline and methylphenidate were significant for the doses 3, 10, 30 and 60 mg/kg, whereas no significant difference was obtained for 0.3 mg/kg methylphenidate. Between-group differences of percentage reduction of D(2) receptor binding were only significant for the groups pretreated with 0.3 and 30 mg/kg methylphenidate, respectively.

Conclusion: Methylphenidate between 0.3 and 60 mg/kg decreased D(2) receptor binding with a maximum reduction after 30 mg/kg. As no between-group differences were evident between the groups pretreated with 3, 10, 30 and 60 mg/kg, it may be inferred that doses ≥ 3 mg/kg were sufficient to induce maximum dopamine concentration in the synaptic cleft. Further investigations are needed in order to clarify whether the variation between subjects can be accounted for by different synaptic mechanisms at the presynaptic binding site.
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http://dx.doi.org/10.1007/s00259-010-1668-xDOI Listing
April 2011

Qualitative and quantitative impact of protective glucocorticoid therapy on the effective 131I half-life in radioiodine therapy for Graves disease.

J Nucl Med 2010 Dec 15;51(12):1917-22. Epub 2010 Nov 15.

Department of Nuclear Medicine, University of Düsseldorf, Düsseldorf, Germany.

Unlabelled: This aim of this retrospective study was to determine the impact of glucocorticoid therapy on the effective (131)I half-life in radioiodine therapy for Graves disease.

Methods: Three hundred fifteen consecutive Graves disease patients undergoing radioiodine therapy at our institution between August 2004 and January 2009 were enrolled. We investigated the influences of thyroid state (hypothyroidism, euthyroidism, hyperthyroidism), antithyroid drug dose before (131)I therapy, thyroid-stimulating hormone receptor antibody (TRAb) level, and qualitative and quantitative factors of prednisolone therapy on the effective (131)I half-life, applying univariate (paired t test) and multivariate (multiple-regression) analyses.

Results: Multivariate analyses revealed independent significant effects of the thyroid metabolic state (P = 0.004), antithyroid drugs (P < 0.001), presence of TRAb (P = 0.004), and glucocorticoids (P = 0.046) on thyroidal radioiodine half-life. Compared with euthyroidism, thyrotoxicosis and hypothyroidism reduced the effective half-life; high doses of antithyroid drugs and high TRAb levels had the same effect. Also, glucocorticoid therapy shortened the effective thyroidal radioiodine half-life in a dose-dependent manner. Pharmacologically, this effect is attributable to the prednisolone-induced increase of renal plasma (131)I clearance and the resulting reduction of plasma (131)I available for reuptake into the thyroid during radioiodine therapy.

Conclusion: Oral treatment with prednisolone results in a reduction of effective thyroidal (131)I half-life in Graves disease, especially at higher doses.
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http://dx.doi.org/10.2967/jnumed.110.080473DOI Listing
December 2010

Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders--results from in vivo imaging studies.

Rev Neurosci 2010 ;21(2):119-39

Clinic of Nuclear Medicine, University Hospital Düsseldorf Heinrich-Heine University Moorenstr. 5, 40225 Dŭsseldorf Germany.

Various factors are discussed in the pathophysiology of anxiety disorders, including dysfunctions of the (DA)ergic, serotonin (5-HT)ergic and GABAergic system. We assessed the contribution of the individual synaptic constituents by subjecting all available in vivo imaging studies on patients with anxiety disorders to a retrospective analysis. On a total of 504 patients with obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder (PD), phobia, or posttraumatic stress-disorder (PTSD) and 593 controls, investigations of VMAT2, DAT, SERT, D1, D2, 5-HTIA, 5-HT2A, GABA(A), and NK1 receptor binding in neostriatum, ventral striatum, thalamus, neocortex, limbic system, cingulate, midbrain/ pons or cerebellum were performed using either PET or SPECT. Separate analyses of the individual disorders showed significant decreases of striatal D2 receptors in OCD (-18%), mesencephalic SERT in OCD (-13%), frontocortical GABAA receptors in PD (-13%) and temporocortical GABAA receptors in GAD (-16%). Pooling of all disorders yielded a significant reduction of mesencephalic SERT (-13%), mesencephalic (-27%) as well as cingulate 5-HT1A receptors (-18%), striatal D2 receptors (-21%) and frontal (-14%), temporal (-14%), occipital (-13%) and cingulate GABAA receptors (-15%). The results show that DA, 5-HT, and GABA play a major role in all subtypes of anxiety disorders. In particular, the findings imply that the regulation state of DA as modulated by GABA and 5-HT may be crucial for the development of anxiety- and compulsion-related disorders. As GABA and 5-HT inhibit DAergic neurotransmission, the reductions of GABAA, 5-HT1A and SERT can be assumed to result in an enhanced activity of the mesolimbic DAergic system. This notion is also reflected by the decrease of striatal D2 receptor binding, which is indicative of an increased availability of synaptic DA.
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http://dx.doi.org/10.1515/revneuro.2010.21.2.119DOI Listing
July 2010

Pretreatment with haloperidol reduces (123)I-FP-CIT binding to the dopamine transporter in the rat striatum: an in vivo imaging study with a dedicated small-animal SPECT camera.

J Nucl Med 2009 Jul 12;50(7):1147-52. Epub 2009 Jun 12.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

Unlabelled: Synaptic dopamine is mainly regulated by presynaptic dopamine transporter (DAT) activity. We hypothesized that variations in synaptic dopamine are reflected by variations of DAT radioligand binding. The effect of haloperidol, which increases synaptic dopamine concentrations, was therefore assessed in the rat striatum using (123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-nortropane ((123)I-FP-CIT) as a DAT radioligand.

Methods: Striatal (123)I-FP-CIT binding was measured in 24 rats under baseline conditions (no pretreatment) and at 1 h after injection of haloperidol or a vehicle (1 mg/kg) using a small-animal SPECT camera.

Results: Baseline equilibrium ratios (V(3)'') were 1.32 +/- 0.24 (mean +/- SD). After the haloperidol injection, V(3)'' decreased to 0.99 +/- 0.38 (P(2-tailed) < 0.0001), corresponding to a mean reduction of DAT binding by 25%.

Conclusion: Our results are indicative of competition between the DAT ligand (123)I-FP-CIT and synaptic dopamine elevated by haloperidol, suggesting that the assessment of (123)I-FP-CIT binding may be suitable to study variations in synaptic dopamine in vivo.
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http://dx.doi.org/10.2967/jnumed.109.061952DOI Listing
July 2009

Investigating the dopaminergic synapse in vivo. II. Molecular imaging studies in small laboratory animals.

Rev Neurosci 2007 ;18(6):473-504

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Germany.

Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinson's disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntington's disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.
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http://dx.doi.org/10.1515/revneuro.2007.18.6.473DOI Listing
May 2008

In-vivo quantification of dose-dependent dopamine transporter blockade in the rat striatum with small animal SPECT.

Nucl Med Commun 2007 Mar;28(3):207-13

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Germany.

Objective: This study investigated dopamine transporter blockade in the rat striatum after treatment with various doses of methylphenidate using a high-resolution small animal SPECT ('TierSPECT') and I-FP-CIT.

Methods: I-FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (3 mg.kg, 10 mg.kg) or vehicle. Rats underwent scanning 2 h after radioligand application. From the spatial resolution of the imaging system and the size of the rat striatum followed that 'true' radioactivity concentrations were underestimated by approximately 50%. From cerebellar and partial volume corrected striatal radioactivity concentrations, striatal equilibrium ratios (V3'') were computed as estimations of the binding potential.

Results: Vehicle-treated animals yielded striatal V3'' values of 3.5+/-0.9 (mean+/-SD). After pre-treatment with 3 mg.kg and 10 mg.kg methylphenidate, striatal V3'' values were reduced to 2.4+/-0.8 (independent t-test, two-tailed, P=0.026) and 1.7+/-0.6 (P<0.001), respectively.

Conclusions: This first in-vivo study of rat dopamine transporter binding after pre-treatment with various doses of methylphenidate showed a dose-dependent reduction of striatal dopamine transporter binding. Results indicate that in-vivo quantification of dopamine transporter binding is feasible with I-FP-CIT and the TierSPECT method. This may be of future relevance for investigating in-vivo binding properties as well as pharmacological profiles of novel agents acting at the dopamine transporter binding site. Moreover, alterations of striatal transporter densities may be investigated in animal models of neurological and psychiatric diseases such as attention-deficit/hyperactivity disorder and Parkinson's disease.
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http://dx.doi.org/10.1097/MNM.0b013e328014a0dfDOI Listing
March 2007

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine--an in vivo imaging study with a dedicated small animal SPECT.

Eur J Nucl Med Mol Imaging 2005 Nov 8;32(11):1305-10. Epub 2005 Jul 8.

Clinic of Nuclear Medicine, Heinrich-Heine University, 40225 Düsseldorf, Germany.

Purpose: This study assessed [123I]iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT.

Methods: Subsequent to baseline quantifications of D2 receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D2 receptors and dopamine transporters, respectively.

Results: Striatal baseline equilibrium ratios (V3'') of [123I]iodobenzamide binding were 1.42+/-0.31 (mean+/-SD). After pre-treatment with haloperidol and methylphenidate, V3'' values decreased to 0.54+/-0.46 (p<0.0001) and 0.98+/-0.48 (p=0.009), respectively.

Conclusion: The decrease in [123I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D2 receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [123I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [123I]iodobenzamide binding to D2 receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.
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http://dx.doi.org/10.1007/s00259-005-1839-3DOI Listing
November 2005

The contribution of small animal positron emission tomography to the neurosciences--a critical evaluation.

Rev Neurosci 2004 ;15(2):131-56

Clinic of Nuclear Medicine, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

This article presents an overview of those animal studies which so far have been performed with dedicated small animal positron emission tomographs in the field of the neurosciences. In vivo investigations focus on energy metabolism, perfusion and receptor/transporter binding in rat models of reinforcement, learning and memory, traumatic brain injury, epilepsy, depression, cardiovascular diseases--such as ischemia and focal stroke--and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. In the majority of studies, important novel aspects arise from the fact that the investigators made use of an option inherent to in vivo studies, namely to conduct longitudinal investigations on the same animals. Relevant findings pertain to the relationship of brain metabolism/perfusion and the cholinergic system, the regulation state of dopamine receptors upon cocaine administration and withdrawal, the regulation state of dopamine receptors and transporters in animal models of Parkinson's and Huntington's disease, and potential treatments of progressive dopaminergic depletion with adenoviral vectors, embryonic grafts, stem cells and nerve growth factors.
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http://dx.doi.org/10.1515/revneuro.2004.15.2.131DOI Listing
July 2004

Quantitative analysis of dopamine D2 receptor kinetics with small animal positron emission tomography.

Methods Enzymol 2004 ;385:228-39

Clinic of Nuclear Medicine, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.

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http://dx.doi.org/10.1016/S0076-6879(04)85013-4DOI Listing
July 2004

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 2003 Apr;44(4):618-24

Nuklearmedizinische Klinik, Universitätsklinikum Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.

Unlabelled: A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D(2) receptor radioligand (18)F-(3-N-methyl)benperidol ((18)FMB) in rat striatum by determining receptor density (B(max)) and affinity (K(d)) in vivo. For validation, K(d) and B(max) additionally were determined in vitro using storage phosphor autoradiography.

Methods: Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of (18)FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of (18)FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis.

Results: PET yielded a K(d) of 6.2 nmol/L and a B(max) of 16 fmol/mg for the striatal D(2) receptor. In vitro, K(d) and B(max) amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of (18)FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively.

Conclusion: K(d) values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B(max) values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B(max) and K(d) may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.
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April 2003

Bilateral increase in striatal dopamine D2 receptor density in the 6-hydroxydopamine-lesioned rat: a serial in vivo investigation with small animal PET.

Eur J Nucl Med Mol Imaging 2003 Mar 17;30(3):390-5. Epub 2002 Dec 17.

Nuklearmedizinische Klinik, Universitätsklinikum Düsseldorf, Germany.

Unilateral destruction of the substantia nigra by local application of 6-hydroxydopamine (6-OHDA) serves as an animal model for Parkinson's disease. In this study, the changes in neostriatal dopamine D(2) receptor density were investigated with a small animal positron emission tomograph (PET) before and after 6-OHDA lesion. PET scans were performed in 14 rats after injection of the D(2) receptor radioligand [(18)F] N-methylbenperidol. After the first scan (day 0), nigrostriatal pathways were lesioned by unilateral injections of 6-OHDA. Further PET scans were performed on days 2 and 14 post-lesion. For both striata, B(max) values were determined from saturation binding curves with non-linear regression analysis. In the striatum ipsilateral to the lesion, B(max) initially amounted to 19.3+/-1. 9 fmol/mg (mean+/-SD) and increased to 19.7+/-2.2 and 29.9+/-5.7 fmol/mg on days 2 and 14 post-lesion, respectively. Contralateral B(max) values increased from 19.2+/-2 fmol/mg prior to the lesion to 21.2+/-2.9 and 28.6+/-5.7 fmol/mg on days 2 and 14, respectively. On day 14, the ipsilateral saturation binding curve differed from the ipsilateral pre-lesion curve (P=0.04; F test). When the contralateral pre-lesion saturation binding curve was compared with the contralateral post-lesion curve on day 14, a P value of 0.08 was obtained. This first serial in vivo imaging study of 6-OHDA-lesioned rats showed a time-dependent increase in striatal D(2) receptor density on both sides, the increase being more pronounced ipsilateral to the lesion. This result implies that compensatory mechanisms in the intact hemisphere contribute to regenerative processes following nigrostriatal dopaminergic denervation. Overall, our findings show the feasibility of repetitive in vivo studies of striatal receptor density with a small animal tomograph. Moreover, the applied in vivo saturation binding technique provides a versatile method for the quantification of time-dependent changes in the concentration of receptor binding sites.
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http://dx.doi.org/10.1007/s00259-002-1056-2DOI Listing
March 2003
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