Publications by authors named "Susanne Nikolaus"

45 Publications

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism.

Mol Brain 2020 08 10;13(1):111. Epub 2020 Aug 10.

Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA.

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury TItpr3/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.
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http://dx.doi.org/10.1186/s13041-020-00649-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418402PMC
August 2020

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

Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala-Preferentially in the hemisphere ipsilateral to the injected nostril.

J Neurochem 2020 04 12;153(2):189-202. Epub 2019 Dec 12.

M et P Pharma AG, Emetten, Switzerland.

This study determined the effects of intranasal pregnenolone (IN-PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG-S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN-PREG on the cholinergic system in the rat brain. In the first experiment, IN-PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN-PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN-PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN-PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN-PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN-PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders.
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http://dx.doi.org/10.1111/jnc.14923DOI Listing
April 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

Acute anxiety disorder, major depressive disorder, bipolar disorder and schizophrenia are related to different patterns of nigrostriatal and mesolimbic dopamine dysfunction.

Rev Neurosci 2019 05;30(4):381-426

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

Dopamine (DA) receptor and transporter dysfunctions play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) in the manic (BDman) or depressive (BDdep) state and schizophrenia (SZ). We performed a PUBMED search, which provided a total of 239 in vivo imaging studies with either positron emission tomography (PET) or single-proton emission computed tomography (SPECT). In these studies, DA transporter binding, D1 receptor (R) binding, D2R binding, DA synthesis and/or DA release in patients with the primary diagnosis of acute AD (n=310), MDD (n=754), BDman (n=15), BDdep (n=49) or SZ (n=1532) were compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BDman, BDdep and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and/or receptor binding sites. In contrast to AD and SZ, in MDD, BDman and BDdep, neostriatal DA function was normal, whereas MDD, BDman, and BDdep were characterized by the increased availability of prefrontal and frontal DA. In contrast to AD, MDD, BDman and BDdep, DA function in SZ was impaired throughout the nigrostriatal and mesolimbocortical system with an increased availability of DA in the striatothalamocortical and a decreased availability in the mesolimbocortical pathway.
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http://dx.doi.org/10.1515/revneuro-2018-0037DOI Listing
May 2019

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

Neurobiol Aging 2018 09 17;69:1-9. Epub 2018 Apr 17.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.005DOI Listing
September 2018

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

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

Neurobiol Learn Mem 2017 Dec 28;146:12-20. Epub 2017 Oct 28.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Germany. Electronic address:

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention.

Results: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala.

Conclusions: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.
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http://dx.doi.org/10.1016/j.nlm.2017.10.015DOI Listing
December 2017

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

Neurobiol Learn Mem 2017 May 3;141:72-77. Epub 2017 Apr 3.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl--aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.
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http://dx.doi.org/10.1016/j.nlm.2017.03.019DOI Listing
May 2017

Different patterns of dopaminergic and serotonergic dysfunction in manic, depressive and euthymic phases of bipolar disorder.

Nuklearmedizin 2017 4;56(5):191-200. Epub 2018 Jan 4.

A variety of alterations in brain neurotransmitter systems has been proposed as the cause of bipolar disorder (BD). We conducted a PUBMED search, which provided a total of 45 in vivo investigations with PET and SPECT, in which binding to serotonin transporter (SERT), 5-HT receptor (R), 5-HTR, dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), DR, DR, muscarinic M2R and nicotinic ß2-nAChR as well as dopamine synthesis and/or dopamine release were assessed in BD patients in the manic (6 studies, 39 patients, 77 controls), depressive (15 studies, 248 patients, 488 controls) or eu- thymic condition (18 studies, 265 patients, 293 controls) and in mixed collectives of BD patients (6 studies, 55 patients, 80 controls). The retrospective analysis revealed a complex pattern of dysregulations within and between neurotransmitter systems, which is causally linked to the acute and euthymic states of BD. While increased mesencephalic, limbic and parietotemporoccipital serotonin and increased frontal dopamine underlie mania, the depressive state is characterized by decreased frontal and limbic serotonin, increased frontal and limbic acetylcholine and increased frontal dopamine. Also in euthymia, no normalization of receptor and transporter densities was observed. Alterations of regulation states of bindings sites, however, act together to achieve a normalization of mesencephalic, limbic and cortical serotonin.
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http://dx.doi.org/10.3413/Nukmed-0893-17-04DOI Listing
November 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

Chronic corticosterone treatment enhances extinction-induced depression in aged rats.

Horm Behav 2016 11 12;86:21-26. Epub 2016 Sep 12.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.
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http://dx.doi.org/10.1016/j.yhbeh.2016.09.003DOI Listing
November 2016

Promnestic effects of intranasally applied pregnenolone in rats.

Neurobiol Learn Mem 2016 09 14;133:185-195. Epub 2016 Jul 14.

Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL 33314, USA; M et P Pharma AG, 6376 Emmetten, Switzerland. Electronic address:

The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration.
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http://dx.doi.org/10.1016/j.nlm.2016.07.012DOI Listing
September 2016

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

Concurrent assessment of memory for object and place: Evidence for different preferential importance of perirhinal cortex and hippocampus and for promnestic effect of a neurokinin-3 R agonist.

Neurobiol Learn Mem 2016 Apr 17;130:149-58. Epub 2016 Feb 17.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

We here explore the utility of a paradigm that allows the simultaneous assessment of memory for object (what) and object location (where) and their comparative predominance. Two identical objects are presented during a familiarity trial; during the test trial one of these is displaced, and a new object is presented in a familiar location. When tested 5 or 80min later, rats explored both the novel and the displaced objects more than two familiar stationary objects, indicating intact memory for both, object and place. When tested 24h later rats explored the novel object more than the displaced familiar one, suggesting that forgetting differently influenced object and place memory, with memory for object being more robust than memory for place. Animals that received post-trial administration of the neurokinin-3 receptor agonist senktide and were tested 24h later, now explored the novel and displaced objects equally, suggesting that the treatment prevented the selective decay of memory for location. Next, animals received NMDA lesions in either the perirhinal cortex or the hippocampus, which are hypothesized to be preferentially involved in memory for objects and memory for place, respectively. When tested 5 or 80min later, the perirhinal cortex lesion group explored the displaced object more, indicating relatively deficient object memory, while the hippocampal lesion led to the opposite pattern, demonstrating comparatively deficient place memory. These results suggest different preferential engagement of the perirhinal cortex and hippocampus in their processing of memory for object and place. This preference test lends itself to application in the comparison of selective lesions of neural sites and projection systems as well as to the assessment of possible preferential action of pharmacological agents on neurochemical processes that subserve object vs place learning.
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http://dx.doi.org/10.1016/j.nlm.2016.02.007DOI Listing
April 2016

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

Different patterns of 5-HT receptor and transporter dysfunction in neuropsychiatric disorders--a comparative analysis of in vivo imaging findings.

Rev Neurosci 2016 Jan;27(1):27-59

Impairment of serotonin receptor and transporter function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ). We conducted a PubMed search, which provided a total of 136 in vivo studies with PET and SPECT, in which 5-HT synthesis, 5-HT transporter binding, 5-HT1 receptor binding or 5-HT2 receptor binding in patients with the primary diagnosis of acute AD, MDD, BD or SZ was compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BD and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and receptor binding sites.
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http://dx.doi.org/10.1515/revneuro-2015-0014DOI Listing
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

The neurokinin-3 receptor agonist senktide facilitates the integration of memories for object, place and temporal order into episodic memory.

Neurobiol Learn Mem 2014 Oct 24;114:178-85. Epub 2014 Jun 24.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined intervals of 1h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (memory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6h later (experiment 3). The senktide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6h later (experiment 4). The vehicle+senktide group showed intact ELM, while the SR142801+senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senktide effect was NK3-R dependent.
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http://dx.doi.org/10.1016/j.nlm.2014.06.009DOI Listing
October 2014

NK₃ receptor agonism reinstates temporal order memory in the hemiparkinsonian rat.

Behav Brain Res 2015 May 11;285:208-12. Epub 2014 Jun 11.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Animals treated with unilateral 6-hydroxydopamine (6-ODHA) injections, an animal model of Parkinson's disease, exhibit deficits in memory for temporal order, but show intact novel object recognition. Since senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in the aged rat and to alleviate scopolamine-induced impairment, the present study aimed to assess possible promnestic effects of senktide in the hemiparkinsonian rat model. Animals received unilateral 6-ODHA microinjections into the medial forebrain bundle. Two weeks later, they were randomly assigned to treatment with vehicle, 0.2, or 0.4 mg/kg senktide. Temporal order memory and place recognition tests were conducted, locomotor activity and turning behavior were assessed in the open field and anxiety-related behavior was measured in the light-dark box. Treatments were administered 30 min prior to behavioral testing with an interval of seven days between tests. The animals treated with 0.2 mg/kg senktide exhibited temporal order memory, unlike the vehicle-treated group. No significant treatment effects were found in the open field and light-dark box. Administration of 0.2 mg/kg senktide may influence the prefrontal cortex and hippocampus, leading to compensations for deficits in memory for temporal order.
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http://dx.doi.org/10.1016/j.bbr.2014.06.006DOI Listing
May 2015

Neurochemical dysfunction in treated and nontreated schizophrenia - a retrospective analysis of in vivo imaging studies.

Rev Neurosci 2014 ;25(1):25-96

To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naïve, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and μ-amino butyric acid (GABA)A receptors. Based on the findings on drug-naïve and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections.
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http://dx.doi.org/10.1515/revneuro-2013-0063DOI Listing
June 2014

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

Key players in major and bipolar depression--a retrospective analysis of in vivo imaging studies.

Behav Brain Res 2012 Jul 29;232(2):358-90. Epub 2012 Mar 29.

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

In the present study, we evaluated the contribution of the individual synaptic constituents of all assessed neurotransmitter systems by subjecting all available in vivo imaging studies on patients with unipolar major depressive disorder (MDD) and bipolar depression (BD) to a retrospective analysis. In acute MDD, findings revealed significant increases of prefrontal and frontal DA synthesis, decreases of thalamic and midbrain SERT, increases of insular SERT, decreases of midbrain 5-HT(1A) receptors and decreases of prefrontal, frontal, occipital and cingulate 5-HT(2A) receptors, whereas, in remission, decreases of striatal D₂ receptors, midbrain SERT, frontal, parietal, temporal, occipital and cingulate 5-HT(1A) receptors and parietal 5-HT(2A) receptors were observed. In BD, findings indicated a trend towards increased striatal D₂ receptors in depression and mania, decreased striatal DA synthesis in remission and decreased frontal D₁ receptors in all three conditions. Additionally, there is some evidence that ventrostriatal and hippocampal SERT may be decreased in depression, whereas in remission and mania elevations of thalamic and midbrain SERT, respectively, were observed. Moreover, in depression, limbic 5-HT(1A) receptors were elevated, whereas in mania a decrease of both cortical and limbic 5-HT(2A) receptor binding was observed. Furthermore, in depression, prefrontal, frontal, occipital and cingulate M2 receptor binding was found to be reduced. From this, a complex pattern of dysregulations within and between neurotransmitter systems may be derived, which is likely to be causally linked not only with the subtype and duration of disease but also with the predominance of individual symptoms and with the kind and duration of pharmacological treatment(s).
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http://dx.doi.org/10.1016/j.bbr.2012.03.021DOI Listing
July 2012

Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions.

Brain Res Bull 2012 Feb 15;87(2-3):340-5. Epub 2011 Nov 15.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitaetstrasse 1, 40225 Düsseldorf, Germany.

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.
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http://dx.doi.org/10.1016/j.brainresbull.2011.11.004DOI Listing
February 2012

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