Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys

Summary The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.     

Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys

In the present study, age-related changes in the striatal dopaminergic system were examined in the living brains of conscious young (6.2 +/- 1.5 years old) and aged (20.2 +/- 2.6 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). L-[beta-(11)C]DOPA and [(11)C]beta-CFT were applied to determine dopamine presynaptic functions such as synthesis rate and transporter (DAT) availability, respectively. Striatal dopamine D(1)- (D(1)R) and D(2)-like receptor (D(2)R) binding were measured with [(11)C]SCH23390 and [(11)C]raclopride, respectively. Although the markers of presynaptic terminals showed parallel age-related declines, the reduction of dopamine synthesis rate measured with L-[beta-(11)C]DOPA was slightly smaller than that of DAT determined with [(11)C]beta-CFT. The binding of [(11)C]raclopride to D(2)R in vivo was significantly reduced with aging, while that of [(11)C]SCH23390 to D(1)R showed no such marked age-related reduction. When the DAT inhibitor GBR12909 (0.5 and 5 mg/kg) was administered, DAT availability, dopamine synthesis, and D(2)R binding were significantly decreased in a dose-dependent manner in both age groups; however, the degrees of the decreases in these parameters were significantly higher in young rather than in aged animals. Dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was increased by administration of GBR12909 in a dose-dependent manner and the degree of the increase in dopamine level decreased with age. These results demonstrate that age-related changes of dopamine neuronal functions were not limited to the resting condition but were also seen in the functional responses to the neurotransmitter modulation.     

猴急慢性实验性变应性脑脊髓炎的病理研究

目的　探讨急、慢性猴 (猕猴类 )实验性变应性脑脊髓炎 (EAE)的病理特点。方法　从EAE猴病程不同阶段进行病理取材 ,制成切片 ,用HE、Bielschowsky改良法、Page法、Holzer法染色及间接免疫荧光法观察CD4、CD8和B淋巴细胞。结果　 ( 1)猴急性EAE脑组织炎症反应重 ,分布在小静脉周围形成血管套 ,以CD4淋巴细胞浸入为主。脱髓鞘病灶微小 ,分布弥散 ,轴突改变轻 ,无出血 ,类似急性播散性脑脊髓炎 (ADEM)。 ( 2 )猴慢性EAE脑组织炎症反应轻 ,分布在血管外周 ,以CD8和B细胞为主。脱髓鞘病灶较大 ,界线清晰 ,呈局灶性分布。病变部位轴突变性严重及轴突丧失 ,有胶质斑块形成 ,与慢性多发性硬化 (MS)的活动期病理改变有惊人的相似。结论　支持猴慢性EAE是MS的优秀模型。另外 ,用相同抗原诱导出不同病程的EAE提示ADEM和MS可能是同一疾病的不同病程 ,或可能是同一种病因 ,而致病程不同。     

Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during the first year of life as measured by positron emission tomography

Recently, advances in spatial resolution have provided the opportunity to utilize positron emission tomography (PET) to examine local cerebral metabolic rates for glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated lCMR(glc) measurements in the same animal. Previous studies have attempted to describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of sedation during the tracer uptake period may influence lCMR(glc). This study was conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross-sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern suggested an increase in lCMR(glc) values between 2 and 8 months of age with decreased metabolism observed at 10-12 months of age in all regions. Peak lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen at the youngest age examined quantitatively (2-3 months). The regions of greatest and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres (90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals supported this developmental pattern, demonstrating the ability to detect changes in cerebral glucose metabolism within animals and the potential for FDG-PET in nonhuman primate models of brain maturation. By determining the normative profile of lCMR(glc) during development in monkeys, future application of FDG-PET will provide the opportunity to longitudinally assess the effects of environmental or pharmacological intervention on the immature brain.     

Mapping of serotonin transporters by positron emission tomography with [11c]DASB in conscious common marmosets: Comparison with rhesus monkeys

The common marmoset (Callithrix jacchus) is unique among the primates in its small body size, reproductive efficacy, and characteristic social behavior, making it useful as an animal model in neuroscientific research. To assess the brain serotonergic systems, we investigated the binding of [¹¹C]‐3‐amino‐4‐(2‐dimetylaminomethyl‐phenylsulfanyl)‐benzonitrile ([¹¹C]DASB) to brain serotonin transporter (SERT) in conscious common marmosets using positron emission tomography (PET), and compared with findings for rhesus monkeys. Both species showed globally similar distribution patterns of [¹¹C]DASB uptake in the brain, with highest activity in the midline of the brain and lowest in the cerebellum, and higher activity in some subcortical regions than in surrounding cortex, while the common marmoset brain showed almost equal or rather higher binding potential (BP) values (BP_ND) in cortical regions and hippocampus, and lower BP_ND than the rhesus monkey brain in some subcortical regions. Test‐retest reproducibility of BP_ND at an interval of several months was high, indicating reliable and stable measurements of serotonin transporters in both species. These results suggest that SERT imaging by PET with [¹¹C]DASB under conscious state is valuable for investigating the physiological serotonergic functions in common marmosets (182). Synapse 2010. © 2010 Wiley‐Liss, Inc.     

慢性实验性变应性猴脑脊髓炎的超微结构改变

目的：探讨自身免疫性中枢神经系统脱髓鞘疾病慢性型的病理特点及其可能机制。方法：成功建立猴实验性态反应性脑脊髓炎模型数年后，根据MR摄片结果位病灶并作分类，然后进行病理取材和电镜观察超微结构。结果：（1）活动性病灶内成片的髓鞘松解、断裂或融合，轴突空泡样变性，皱缩或消失，少突胶质细胞变性，未见淋巴细胞浸润，仅见散在巨噬细胞，伴明显的间质水肿；（2）可疑活动性病灶内见部分髓鞘内板松解，其内轴突有较度空泡样变，亦见少突胶质细胞变性，散在巨噬细胞，未见淋巴瘤浸润，结论：慢性EAE的病理改变不仅有髓鞘的变性，同时轴突的病变也十分明显。     

Striatal dopamine metabolism in living monkeys examined by positron emission tomography

Positron emission tomography, using the dopa analogue [18F]6-fluoro-L-dopa, has been used to depict the neostriatum in living monkeys. The amount of 18F that accumulated preferentially in the striatum could be augmented by a peripheral decarboxylase inhibitor. Striatal 18F could also be discharged with reserpine. This is the first time that the regional distribution of a neurotransmitter has been demonstrated in monkeys.     

Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of Rhesus monkeys studied with positron emission tomography

ABSTRACT— The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D₂-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D₂-dopamine receptors in the striatal area. Raclopride was selectively bound to the D₂-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, k_on and number of receptors, B_max, varied from 0.02–0.07 min^-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the B_max values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.     

食蟹猴年龄相关的运动功能减退及其与纹状体多巴胺转运体的关系

目的研究食蟹猴老化过程中运动行为和脑内纹状体多巴胺系统功能变化及两者之间的相关关系。方法选取4岁、10岁和15岁3个年龄组的健康食蟹猴共29只,利用计算机化的网络摄像头视频检测系统和行为分析软件连续采集和分析每个动物8h随意运动活动总量,各年龄组分别选取4只动物用多巴胺转运体(DAT)配体99mTc-TRODAT-1结合单光子发射体层摄影术(SPECT)显像观察脑内纹状体多巴胺转运体放射性摄取率的变化。结果在4岁、10岁和15岁年龄组,8h随意运动活动总量(×106)分别为5·00±1·93,3·28±1·02,2·79±0·67,在10岁和15岁较之4随年龄组分别降低了34·50%和55·71%(P<0·05,P<0·01),但此两个年龄组运动活动总量无显著差异(P>0·05);纹状体99mTc-TRODAT-1放射性摄取率分别为2·98±0·08,2·56±0·12和2·27±0·35,10岁和15岁较之4随年龄组分别降低了14·00%和25·60%,但仅4岁与15岁年龄组存在显著相关关系(P<0·01)。二者均随着年龄的增长呈逐渐减低的趋势,直线回归分析显示两者分别与年龄呈负相关关系(r=-0·57,P=0·001;r=-0·86,P<0·01)。8h随意运动活动总量与纹状体99mTc-TRODAT-1放射性摄取率呈显著的正相关关系(r=0·70,P<0·05)。结论正常食蟹猴老化过程中,脑内多巴胺神经系统功能的减退伴随着运动行为的减少,两者之间的相关关系进一步佐证了运动功能的减退可能是由于纹状体内多巴胺神经元功能减退所致。     

Application of positron emission tomography to determine cerebral glucose utilization in conscious infant monkeys.

Cerebral glucose metabolism has been used as a marker of cerebral maturation and neuroplasticity. In studies addressing these issues in young non-human primates, investigators have used positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) to calculate local cerebral metabolic rates of glucose (1CMRG1c). Unfortunately, these values were influenced by anesthesia. In order to avoid this confounding factor, we have established a method that permits reliable measurements in young conscious vervet monkeys using FDG-PET. Immature animals remained in a conscious, resting state during the initial 42 min of FDG uptake as they were allowed to cling to their anesthetized mothers. After FDG uptake, animals were anesthetized and placed in the PET scanner with data acquisition beginning at 60 min post-FDG injection. FDG image sets consisted of 30 planes separated by 1.69 mm, parameters sufficient to image the entire monkey brain. Our method of region-of-interest (ROI) analysis was assessed within and between raters and demonstrated high reliability (P < 0.001). To illustrate that our method was sensitive to developmental changes in cerebral glucose metabolism, quantitative studies of young conscious monkeys revealed that infant monkeys 6-8 months of age exhibited significantly higher 1CMRG1c values (P < 0.05) in all regions examined, except sensorimotor cortex and thalamus, compared to monkeys younger than 4 months of age. This method provided high resolution images and 1CMRG1c values that were reliable within age group. These results support the application of FDG-PET to investigate questions related to cerebral glucose metabolism in young conscious non-human primates.     

Brain energy metabolism and dopaminergic function in Huntington's disease measured in vivo using positron emission tomography

A 48-year-old man with typical Huntington's disease was investigated with computed tomography (CT) and positron emission tomography. Regional cerebral blood flow, oxygen extraction, oxygen and glucose utilisation, L-Dopa uptake, and dopamine (D2) receptor binding were measured using several positron-labelled tracers. CT showed slight atrophy of the head of caudate but no cortical atrophy, although distinct frontal lobe dysfunction was present on psychometric testing. Oxygen and glucose metabolism and cerebral blood flow were decreased in the striata and to a lesser extent in frontal cortex. Cerebral blood flow was in the low normal range throughout the remainder of the brain. A normal metabolic ratio was found in all regions, since the changes in glucose utilisation paralleled those in oxygen consumption. The capacity of the striatum to store dopamine as assessed by L-[18F]-fluorodopa uptake was normal, but dopamine (D2) receptor binding was decreased when compared to normal subjects.     

In vivo imaging of neuromodulation using positron emission tomography: Optimal ligand characteristics and task length for detection of activation

Considerable evidence suggests that cognitive state affects local levels of neurotransmitter in the brain. We introduce a compartment model of neuroreceptor ligand kinetics to describe the effect of change in cognitive state on positron emission tomography (PET) signal dynamics. The model is used to establish optimal experimental conditions, timing of activation, and ligand characteristics, for detecting cognitive activation. The model, which follows free and bound endogenous neurotransmitter, describes the PET curve predicted for a single injection of radioligand in the presence or absence of activation. Activation was conceptualized as the performance of a task that raises the level of neurotransmitter that competes for receptor sites with the radioligand. Simulating the dopamine system, for example, required making assumptions regarding the kinetic rate constants for binding/dissociation of endogenous dopamine to/from the receptor and dopamine concentrations in the synapse. Simulations suggest that activation of dopamine should be detectable with PET and the D2 receptor ligand [¹¹C]raclopride, although this ligand might not be optimal. Aspects of experimental design can be modified to optimize the likelihood of detecting neurotransmitter changes. The ideal radioligand for these studies should bind irreversibly to its receptor. Furthermore, the task should commence at injection time and last for at least 7 minutes. Optimal task duration depends on the dynamics of free radioligand in the tissue and can be determined via model simulations for any well-characterized receptor ligand. Flow effects were shown to be distinguishable from those of neurotransmitter activation. General principles regarding desirable ligand characteristics and activation timing held for both the D2 receptor and the dopamine transporter site. © 1995 Wiley-Liss, Inc.     

Brain dopaminergic mechanisms in Parkinson's disease evaluated by positron emission tomography

Abstract– The meso-striatal dopamine neurons, essential for the automated control of movements, are primarily affected in patients with P.D. Direct study of the role of this pathway in states of disease has not been possible until recently and the application of PET for the in vivo investigation of dopaminergic mechanisms may serve to demonstrate the potential of the technique.
One basic idea has been to work out methods to investigate multiple aspects of dopaminergic function, i.e. presynaptic mechanisms such as re-uptake sites and synthesis of neurotransmitter as well as postsynaptic such as receptor properties. Furthermore, efforts have been made to evaluate dopamine degradating enzymes. Preclinical PET-investigations have regularly been performed in Rhesus monkeys and the hemiparkinsonian model produced by infusing MPTP into one internal carotid artery has been of great value to characterize new ¹¹C-labelled tracers. Today ¹¹C–(+)-nomifensine is used to give a measure of dopamine re-uptake sites, probably reflecting nerve terminals. ¹¹C-labelled L-dopa has now been introduced and can be expected to replace ¹⁸F-L-fluorodopa as a physiological tracer for precursor transport and transmitter synthesis. Several ligands are available for the quantitation of dopamine receptors – ¹¹C-N-methylspiperone and ¹¹C-raclopride have been used in our studies. ¹¹C-L-selegiline and its "inactive'D-form have been used in clinical PET-studies aimed to evaluate the enzyme MAO-B. A summary of in vivo information of dopaminergic mechanisms in P.D. obtained using the above-mentioned tracers and PET is presented.     

In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography.

BACKGROUND: Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS: Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS: Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS: Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.     

Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

Summary The effects of pharmacological intervention on brain muscarinic cholinergic receptor (mAChR) binding were assessed in seven patients with Parkinson's disease by positron emission tomography and carbon-11 labelled N-methyl-4-piperidyl benzilate ([¹¹C]NMPB). [¹¹C]NMPB was injected twice, approximately 2 hours apart, in each patient, to assess the effect of single doses of 4 mg of trihexyphenidyl (n=5) or 400 mg of L-dopa with 57 mg of benserazide (n=2) on the binding parameter of mAChRs (K₃). There was a mean 28% inhibition of K₃ values in the brain in the presence of trihexyphenidyl, which was assumed to reflect mAChR occupancy. No significant change in K₃ was observed in the presence of L-dopa. This study demonstrates the feasibility of measuring mAChR occupancy by an anticholinergic medication with PET.     

Age-related changes of dopamine D1-like and D2-like receptor binding in the F344/N rat striatum revealed by positron emission tomography and in vitro receptor autoradiography

To clarify age-related changes in dopamine D1-like and D2-like receptor binding in the striatum, positron emission tomography (PET) and in vitro receptor autoradiography (in vitro ARG) were performed using F344/N rats of various ages (6, 12, 18, and 24 months). In the PET study, [11C]SCH23390 and [11C]raclopride were used to image dopamine D1-like receptors and dopamine D2-like receptors, respectively, while [3H]SCH23390 and [3H]raclopride were used for the in vitro ARG study. With PET, we calculated the binding potential (= k3/k4, Bmax/Kd) of [11C]SCH23390 and [11C]raclopride in the striatum according to the curve fitting (CF) and the Logan plot (LP) methods. The binding potential of [11C]SCH23390 in the striatum demonstrated significant decrease as a function of age (max. decrease -26%) by the LP method, while this was not observed in the data analyzed by the CF method. In contrast, the binding potential of [11C]raclopride in the striatum decreased significantly with age by both the CF (max. decrease -28%) and the LP (max. decrease -36%) methods. However, no significant difference by either method was observed in rats between 6 and 12 months old using either ligand. In the in vitro ARG study, the specific binding (fmol/mg tissue) of [3H]SCH23390 and [3H]raclopride in the striatum were determined. Both [3H]SCH23390 and [3H]raclopride binding declined considerably with age as noted by comparing 12, 18, and 24-month-old rats against those 6 months old (max. decrease -29% and -31%, respectively). The substantial difference in binding shown in 12-month-olds in comparison with 6-month-olds using either ligand with in vitro ARG was in contrast with the PET results. These distinctions between the PET and the in vitro ARG studies may be attributed to the receptor microenvironment created under these experimental conditions. The results indicate that PET with LP analysis is useful in obtaining age-related changes of D1-like and D2-like receptor binding in the striatum of living rats.     

Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: a positron emission tomography study in conscious monkeys.

BACKGROUND: Positron emission tomography (PET) studies of methamphetamine (METH) abusers suggest that psychotic symptoms of METH abusers may be attributable to the reduction of dopamine transporters (DAT) in the human brain. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with METH abuse. METHODS: Using a PET study in conscious monkeys, we investigated whether the second generation antibiotic minocycline could protect against the reduction of DAT in monkeys treated with METH (2 mg/kg x 3, 3-hour intervals). RESULTS: Pretreatment and subsequent administration of minocycline significantly attenuated the reduction of DAT in the striatum of monkeys treated with METH. Furthermore, posttreatment and subsequent administration of minocycline also significantly attenuated the reduction of DAT. In contrast, repeated administration of minocycline alone did not alter the density of DAT in the striatum of monkeys treated with METH. CONCLUSIONS: Our findings suggest that minocycline protects against METH-induced neurotoxicity in the monkey brain. Therefore, minocycline is likely to be a promising therapeutic agent for the treatment of several symptoms associated with METH use in humans.     

6-[18F]fluoro-L-dopa metabolism in MPTP-treated monkeys: assessment of tracer methodologies for positron emission tomography

6-[18F]Fluoro-L-DOPA (FDOPA) is an L-DOPA analog that is used to assess the functional integrity of central dopaminergic systems in vivo with positron emission tomography (PET). FDOPA metabolites from putamen of normal and MPTP-treated monkeys were characterized to correlate FDOPA metabolism changes with those of the endogenous dopamine system. In MPTP-lesioned putamen, 6-[18F]fluorodopamine and dopamine levels were less than 2% those of controls. Increases in endogenous dopamine metabolism were reflected by similar increases in 6-[18F]fluorodopamine metabolites. These results suggest that changes in the central dopamine system biochemistry can be monitored in vivo with FDOPA and PET.