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In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.
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Receptor de Serotonina 5-HT1A , Estriado Ventral , Ratas , Animales , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
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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Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Actividad Motora , Receptores de Dopamina D2/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Dopaminérgicos/farmacología , Endocitosis , Exocitosis , Conducta Exploratoria , Levodopa/farmacología , Masculino , Unión Proteica , Ratas , Ratas Wistar , Sinapsis/metabolismoRESUMEN
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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Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D2/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Benzamidas , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/complicaciones , Pirrolidinas , TropanosRESUMEN
PURPOSE: For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat. METHODS: Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography. RESULTS: DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP. CONCLUSIONS: DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.
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Anfetaminas , Encéfalo , Dopamina , Serotonina , Animales , Ratas , Serotonina/metabolismo , Masculino , Dopamina/metabolismo , Anfetaminas/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ketanserina/farmacología , Ketanserina/análogos & derivados , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratas WistarRESUMEN
Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3â¯mg/kg), WAY100,635 (0.4â¯mg/kg), DOI (0.1â¯mg/kg), ALT (1â¯mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Conducta Exploratoria , Reconocimiento en Psicología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Emociones/efectos de los fármacos , Emociones/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratas WistarRESUMEN
PURPOSE: Left ventricular assisting device (LVAD) is a vital mechanical circulatory assist device for patients with end-stage heart disease, serving as either a bridge to transplantation or palliative destination therapy. Yet device infection represents a major lethal complication, warranting a multi-step, complex therapy approach including an urgent device exchange or heart transplantation. Still, timely diagnosis of site and extent of VAD-specific infection for a proper therapy planning poses challenges in regular clinical care. This single-center, retrospective study aimed to evaluate the impact of volumetric PET parameters with different thresholding compared to semiquantitative PET parameters for accurate diagnosis of VAD-specific infection. PROCEDURES: Seventeen patients (1 female, 16 males; mean age 57 ± 11 years) underwent [18F]FDG imaging for suspected VAD-specific infection between April 2013 and October 2023. Various metabolic and volumetric PET parameters with different thresholding were collected for specific LVAD components including driveline entry point, subcutaneous driveline, pump pocket, inner cannula and outflow tract. Microbiology and clinical follow-up were used as the final diagnosis standard. RESULTS: Nine of eleven patients with VAD-specific infection underwent urgent heart transplantation, and one had a surgical revision of LVAD. Two patients had non-VAD specific infections, and two had non-VAD related infections. Metabolic burden determination using a fixed absolute threshold provided the best outcome compared to relative thresholding or other metabolic SUV parameters. The total metabolic tumor volume (MTV) cutoff value was 9.3 cm3, and the corresponding sensitivity, specificity, accuracy, and AUC were 90.0%, 71.43%, 82.5%, and 0.814 (95% CI 0.555-0.958), respectively. The total lesion glycolysis (TLG) was 30.6, and the corresponding sensitivity, specificity, accuracy, and AUC were 90.0%, 71.4%, 82.5%, and 0.829 (95% CI 0.571-0.964), respectively. CONCLUSIONS: Volumetric PET parameters with fixed absolute thresholding appear to be a valuable auxiliary tool in the evaluation of [18F]FDG imaging to enhance the diagnostic accuracy of VAD-specific infection.
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BACKGROUND: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. METHODS: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56-85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. RESULTS: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. CONCLUSION: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.
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Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. D2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [123I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.
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Dopamina , Conducta Exploratoria , Piperazinas , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Dopamina/metabolismo , Conducta Exploratoria/efectos de los fármacos , Piperazinas/farmacología , Piridinas , Ratas , Receptor de Serotonina 5-HT1A , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
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-2ß-carbomethoxy-3ß-(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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Cuerpo Estriado , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Tomografía de Emisión de Positrones , Sinapsis/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Adrenérgicos/toxicidad , Animales , Benzamidas/farmacocinética , Mapeo Encefálico , Cuerpo Estriado/citología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Mesilatos/farmacocinética , Oxidopamina/toxicidad , Unión Proteica/efectos de los fármacos , Pirrolidinas/farmacocinética , Ratas , Sinapsis/efectos de los fármacos , Tropanos/farmacocinéticaRESUMEN
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)â³) were computed as an estimation of the binding potential. RESULTS: After methylphenidate, striatal V(3)â³ 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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Yodobencenos/metabolismo , Metilfenidato/farmacología , Receptores de Dopamina D2/metabolismo , Tomografía Computarizada de Emisión de Fotón Único , Animales , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brain. Altanserin (ALT) and 2,5-dimethoxy-4-iodoamphetamine (DOI) act as 5-HT2AR antagonist and agonist, respectively. In the present study, we assessed the effects of ALT and DOI on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. Methods: D2/3R binding was determined after systemic application of ALT (10 mg/kg) or DOI (0.5 mg/kg) and the respective vehicles [dimethyl sulfoxide (DMSO) and 0.9% saline (SAL)] with [123I]IBZM as a single-photon emission computed tomography (SPECT) radioligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after 5-HT2AR antagonistic or agonistic treatment, motor/exploratory behaviors were assessed for 45 (ALT) or 30 min (DOI) in an open field. Additional rats underwent behavioral measurements after injection of DMSO or SAL. Results: ALT increased D2/3R binding in the ventral hippocampus relative to vehicle, while DOI augmented D2/3R binding in caudate putamen, frontal cortex, motor cortex, and ventral hippocampus. The 5-HT2AR agonist as well as antagonist decreased parameters of motor activity and active exploration. However, ALT, in contrast to DOI, decreased explorative head-shoulder motility and increased sitting. Conclusions: The regional increases of D2/3R binding after ALT and DOI (90 and 75 min post-challenge) may be conceived to reflect decreases of synaptic DA. The reductions of motor/exploratory activities (min 1-45 and min 1-30 after challenge with ALT and DOI, respectively) contrast the regional reductions of D2/3R binding, as they indicate elevated DA levels at the time of behavioral measurements. It may be concluded that ALT and DOI modulate DA in the individual regions of the nigrostriatal and mesolimbocortical pathways differentially and in a time-dependent fashion.
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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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Trastornos de Ansiedad/patología , Dopamina/metabolismo , Trastorno Obsesivo Compulsivo/patología , Serotonina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Trastornos de Ansiedad/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Humanos , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/metabolismo , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , CintigrafíaRESUMEN
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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Bicuculina/farmacología , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Receptores de GABA-A/metabolismo , Animales , Bicuculina/metabolismo , Humanos , Muscimol/metabolismo , Muscimol/farmacología , Núcleo Accumbens/efectos de los fármacos , Ratas , Receptores de GABA-A/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
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.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Haloperidol/administración & dosificación , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos/farmacocinética , Animales , Antipsicóticos/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Distribución Tisular/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único/instrumentación , Tomografía Computarizada de Emisión de Fotón Único/veterinariaRESUMEN
PURPOSE: The present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine D2/3R binding in relation to motor and exploratory activity in the rat. METHODS: D2/3R binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40â¯mg/kg) using [123I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30â¯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: 40â¯mg/kg AMA reduced D2/3R binding in nucleus accumbens, caudateputamen and thalamus, while 10â¯mg/kg decreased D2/3R 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 15â¯min post-challenge. CONCLUSIONS: Results showed reductions of D2/3R 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.
Asunto(s)
Amantadina/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Conducta Exploratoria , Sistema Límbico/efectos de los fármacos , Actividad Motora , Animales , Cuerpo Estriado/metabolismo , Sistema Límbico/metabolismo , Masculino , Ratas , Ratas Wistar , Receptores Dopaminérgicos/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
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 D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]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 D2/3R 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 D2/3R 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 D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R 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.
Asunto(s)
Amantadina/metabolismo , Cicloserina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Sustancia Negra/metabolismo , Área Tegmental Ventral/metabolismo , Animales , Dopamina/metabolismo , Conducta Exploratoria , Masculino , Actividad Motora , Núcleo Accumbens/metabolismo , Unión Proteica , Ratas , Ratas Wistar , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Tálamo/metabolismoRESUMEN
Purpose: The present study assessed the effects of the GABAA receptor (R) agonist muscimol (MUS), and the GABAAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat. Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]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. Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012). In all these areas, except for the thalamus, D2/3R 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, D2/3R binding was significantly elevated in caudateputamen (p = 0.022) and thalamus (p = 0.047) relative to baseline. D2/3R 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. Conclusions: 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.
RESUMEN
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.
Asunto(s)
Diagnóstico por Imagen/métodos , Dopamina/metabolismo , Sinapsis/metabolismo , Animales , Animales de Laboratorio , Transmisión SinápticaRESUMEN
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.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Neostriado/diagnóstico por imagen , Neostriado/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Algoritmos , Animales , Cerebelo/irrigación sanguínea , Cerebelo/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Interpretación Estadística de Datos , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Glándula de Harder/diagnóstico por imagen , Masculino , Metilfenidato/farmacología , Cuello/irrigación sanguínea , Neostriado/efectos de los fármacos , Radiofármacos , Ratas , Ratas Wistar , Glándulas Salivales/diagnóstico por imagen , TropanosRESUMEN
PURPOSE: The present study assessed the influence of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline on neostriatal dopamine D2 receptor binding in relation to motor and exploratory behaviors in the rat. METHODS: D2 receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D2 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 [123I]S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([123I]IBZM). For baseline and challenges, striatal equilibrium ratios (V3â³) were computed as estimation of the binding potential. RESULTS: Muscimol but not bicuculline reduced D2 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 D2 receptor imaging studies. The results indicate direct GABAergic control over D2 receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.