Suppressive effects of ketamine on auditory steady-state responses in intact, awake macaques: A non-human primate model of schizophrenia.

Auditory steady-state responses (ASSRs) are recurrent neural activities entrained to regular cyclic auditory stimulation. ASSRs are altered in individuals with schizophrenia, and may be related to hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor. Noncompetitive NMDA receptor antagonists, including ketamine, have been used in ASSR studies of rodent models of schizophrenia. Although animal studies using non-human primates are required to complement rodent studies, the effects of ketamine on ASSRs are unknown in intact awake non-human primates. In this study, after administration of vehicle or ketamine, click trains at 20-83.3 Hz were presented to elicit ASSRs during recording of electroencephalograms in intact, awake macaque monkeys. The results indicated that ASSRs quantified by event-related spectral perturbation and inter-trial coherence were maximal at 83.3 Hz after vehicle administration, and that ketamine reduced ASSRs at 58.8 and 83.3 Hz, but not at 20 and 40 Hz. The present results demonstrated a reduction of ASSRs by the NMDA receptor antagonist at optimal frequencies with maximal responses in intact, awake macaques, comparable to ASSR reduction in patients with schizophrenia. These findings suggest that ASSR can be used as a neurophysiological biomarker of the disturbance of gamma-oscillatory neural circuits in this ketamine model of schizophrenia using intact, awake macaques. Thus, this model with ASSRs would be useful in the investigation of human brain pathophysiology as well as in preclinical translational research.

Characteristics of auditory steady-state responses to different click frequencies in awake intact macaques.

BACKGROUND: Auditory steady-state responses (ASSRs) are periodic evoked responses to constant periodic auditory stimuli, such as click trains, and are suggested to be associated with higher cognitive functions in humans. Since ASSRs are disturbed in human psychiatric disorders, recording ASSRs from awake intact macaques would be beneficial to translational research as well as an understanding of human brain function and its pathology. However, ASSR has not been reported in awake macaques. RESULTS: Electroencephalograms (EEGs) were recorded from awake intact macaques, while click trains at 20-83.3 Hz were binaurally presented. EEGs were quantified based on event-related spectral perturbation (ERSP) and inter-trial coherence (ITC), and ASSRs were significantly demonstrated in terms of ERSP and ITC in awake intact macaques. A comparison of ASSRs among different click train frequencies indicated that ASSRs were maximal at 83.3 Hz. Furthermore, analyses of laterality indices of ASSRs showed that no laterality dominance of ASSRs was observed. CONCLUSIONS: The present results demonstrated ASSRs, comparable to those in humans, in awake intact macaques. However, there were some differences in ASSRs between macaques and humans: macaques showed maximal ASSR responses to click frequencies higher than 40 Hz that has been reported to elicit maximal responses in humans, and showed no dominant laterality of ASSRs under the electrode montage in this study compared with humans with right hemisphere dominance. The future ASSR studies using awake intact macaques should be aware of these differences, and possible factors, to which these differences were ascribed, are discussed.

Impact of free energy of polymers on polymorphism of polymer-grafted nanoparticles.

Colloidal crystals have gathered wide attention as a model material for optical applications because of their feasibility in controlling the propagation of light by their crystal structure and lattice spacing as well as the simplicity of their fabrication. However, due to the simple interaction between colloids, the colloidal crystal structures that can be formed are limited. It is also difficult to adjust the lattice spacing. Furthermore, colloidal crystals are fragile compared to other crystals. In this study, we focused on polymer-grafted nanoparticles (PGNP) as a possible solution to these unresolved issues. We expected that PGNPs, composed of two distinct layers (the hard core of a nanoparticle and the soft corona of grafted polymers on the surface), will demonstrate similar behaviors as star polymers and hard spheres. We also predicted that PGNPs may exhibit polymorphism because the interaction between PGNPs strongly depends upon their grafting density and the length of the grafted polymer chains. Moreover, we expected that crystals made from PGNPs will be structurally tough due to the entanglement of grafted polymers. From exploration of crystal polymorphs of PGNPs by molecular dynamics simulations, we found face-centered cubic (FCC)/hexagonal close-packed (HCP) and body-centered cubic (BCC) crystals, depending on the length of the grafted polymer chains. When the chains were short, PGNPs behaved like hard spheres and crystals were arranged in FCC/HCP structure, much like the phase transition observed in an Alder transition. When the chains were long enough, the increase in the free energy of grafted polymers was no longer negligible and crystals were arranged in BCC structure, which has a lower density than FCC/HCP. When the chains were not too short or long, FCC/HCP structures were first observed when the volume fraction of system was small, but a phase transition occurred when the system was further compressed and the crystals arranged themselves in a BCC structure. These results most likely have laid strong foundations for future simulations and experimental studies of PGNP crystals.

Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines.

BACKGROUND: High inflammation status despite an absence of known infection characterizes a subpopulation of people with schizophrenia who suffer from more severe cognitive deficits, less cortical grey matter, and worse neuropathology. Transcripts encoding factors upstream of nuclear factor kappa B (NF-κB), a major transcriptional activator for the synthesis of pro-inflammatory cytokines, are increased in the frontal cortex in schizophrenia compared to controls. However, the extent to which these changes are disease-specific, restricted to those with schizophrenia and high-neuroinflammatory status, or caused by loss of a key NF-κB inhibitor (HIVEP2) found in schizophrenia brain, has not been tested. METHODS: Post-mortem prefrontal cortex samples were assessed in 141 human brains (69 controls and 72 schizophrenia) and 13 brains of wild-type mice and mice lacking HIVEP2 (6 wild-type, 7 knockout mice). Gene expression of pro-inflammatory cytokines and acute phase protein SERPINA3 was used to categorize high and low neuroinflammation biotype groups in human samples via cluster analysis. Expression of 18 canonical and non-canonical NF-κB pathway genes was assessed by qPCR in human and mouse tissue. RESULTS: In humans, we found non-canonical upstream activators of NF-κB were generally elevated in individuals with neuroinflammation regardless of diagnosis, supporting NF-κB activation in both controls and people with schizophrenia when cytokine mRNAs are high. However, high neuroinflammation schizophrenia patients had weaker (or absent) transcriptional increases of several canonical upstream activators of NF-κB as compared to the high neuroinflammation controls. HIVEP2 mRNA reduction was specific to patients with schizophrenia who also had high neuroinflammatory status, and we also found decreases in NF-κB transcripts typically induced by activated microglia in mice lacking HIVEP2. CONCLUSIONS: Collectively, our results show that high cortical expression of pro-inflammatory cytokines and low cortical expression of HIVEP2 in a subset of people with schizophrenia is associated with a relatively weak NF-κB transcriptional signature compared to non-schizophrenic controls with high cytokine expression. We speculate that this comparatively milder NF-κB induction may reflect schizophrenia-specific suppression possibly related to HIVEP2 deficiency in the cortex.

Non-invasive electroencephalographical (EEG) recording system in awake monkeys.

BACKGROUND: Human clinical studies reported that several electroencephalographical (EEG) parameters can be used as biomarkers of psychiatric disorders. EEGs recorded from non-human primates (monkeys) is useful for understanding of human pathologies of psychiatric disorders and development of new therapeutic agents. NEW METHODS: In this study, we expand a previous non-invasive head holding system with face masks for awake monkeys to be applied to scalp EEG recording. The new design of a head holding system allows to attach scalp EEG electrodes on the positions comparable to human electrode placement and to present auditory stimuli. RESULTS: With this system, we could record auditory evoked potentials (AEPs) in auditory sensory gating and oddball paradigms, which are often used as biomarkers of psychiatric disorders in animal models and human patients. The recorded AEPs were comparable to previous human clinical data. COMPARISON WITH EXISTING METHODS: Compared with previous non-invasive head holding systems, top, side (cheek and ears), and rear of the head can be open for attachment of EEG electrodes and auditory stimulation in the present system. CONCLUSIONS: The results suggest that the present system is useful in EEG recording from awake monkeys. Furthermore, this system can be applied to eye-tracking and chronic intra-cerebral recording experiments.

Surface Fluctuations Dominate the Slow Glassy Dynamics of Polymer-Grafted Colloid Assemblies.

Colloids grafted with a corona layer of polymers show glassy behavior that covers a wide range of fragilities, with this behavior being tunable through variations in grafting density and grafting chain length. We find that the corona roughness, which is maximized for long chain lengths and sparse grafting, is directly correlated to the concentration-dependence of the system relaxation time (fragility). Relatively rougher colloids result in stronger liquids because their rotational motions become orientationally correlated across the whole system even at low particle loadings leading to an essentially Arrhenius-like concentration-dependence of the relaxation times near the glass transition. The smoother colloids do not show as much orientational correlation except at higher densities leading to fragile behavior. We therefore propose that these materials are an ideal model to study the physical properties of the glass transition.

Accurate estimation of the polymer coverage of hairy nanoparticles.

Understanding and predicting the mechanisms underpinning the self-assembly of polymer-grafted nanoparticles (PGNPs) are important for controlling the engineering applications of these novel materials. The self-assembly of these materials is driven by their surfactancy, i.e., by the fact that the (inorganic) nanoparticles energetically dislike the (organic) polymer tethers. In previous work we developed a model in which a grafted polymer chain was treated as a rigid equivalent sphere (ES) which was impenetrable to the NPs, but completely penetrable to other ESs. This description, along with a geometric analogy with patchy particles, allowed us to facilely explain the self-assembly of PGNPs. However, since we model an ES as being completely penetrable to other ESs but impenetrable to the NPs the physical correspondence between a "real" grafted polymer and an ES is not clear. The application of the ES model to experiments and to computer simulations has therefore seen limited success, and only qualitative agreement has been obtained. In this paper, we develop a more realistic description, termed the modified ES (mES) model, based on the work of Daoud and Cotton on curved polymer brushes, which takes the impenetrability of the individual chain monomers into account. While this approach increases the complexity of our formalism, we find that the resulting mES model quantitatively captures computer simulation results on the structure of the PGNPs and also quantitatively explains their self-assembly over a broad range of conditions.

Role of Grafting Mechanism on the Polymer Coverage and Self-Assembly of Hairy Nanoparticles.

It is now well-accepted that controlling the spatial dispersion of nanoparticles (NPs), which can be achieved by grafting them with polymers of different chain lengths and grafting densities, is central to optimizing the thermomechanical properties of the resulting polymer nanocomposites. In general, there are two methods for creating such polymer-grafted NPs: "grafting to" and "grafting from". The conventional wisdom is that the "grafting from" mechanism, where monomer-sized initiator/functional groups are attached to the surface followed by growing the chains, allows for higher polymer grafting densities and hence a more uniform polymer coverage of the NP surface. Here, we perform calculations and instead show that the "grafting to" strategy surprisingly leads to a more uniform polymer coverage of the NP surface at a given grafting density since the brush is formed while respecting the excluded volume constraints of the previously grafted chains. This conclusion is especially clear in the limit of low-to-moderate grafting density. Thus, at a given grafting density, the "grafting to" mechanism leads to an enhanced miscibility of the NPs in the matrix (which has the same chemistry as the grafts) and lower propensity to create self-assembled structures. Another important factor is that the dispersity in the number of grafted chains on the NPs is also smaller in the case of "grafting to" systems, thus leading to better defined materials. These two conclusions imply that the "grafting to" mechanism may provide better control over the NP dispersion state and hence the thermomechanical properties of polymer nanocomposites.

Supercoiling transformation of chemical gels.

The swelling/deswelling behavior of chemical gels has been an unsolved problem disputed over for a long time. The Obukhov-Rubinstein-Colby model depicts the influence that swelling/deswelling has on elasticity, but its physical picture is too complicated to be sufficiently validated by experiment. In this study, we use molecular dynamics simulation to verify the validity of the molecular picture of network strands predicted by the Obukhov-Rubinstein-Colby model. We conclude that the physical picture of the Obukhov-Rubinstein-Colby model is reasonable, and furthermore the simulation can reveal the details of conformational changes in network strands during the supercoiling transformation. Our findings not only reveal the validity, but also give a better understanding of the dynamics of the swelling/deswelling behavior of chemical gels.

Quantitative analogy between polymer-grafted nanoparticles and patchy particles.

We establish a quantitative analogy between polymer grafted nanoparticles (PGNPs) and patchy nanoparticles (NPs). Over much of the experimentally relevant parameter space, we show that PGNPs behave quantitatively like Janus NPs, with the patch size having a universal dependence on the number of grafts and the ratio of the size of the NPs to the grafted chain size. The widely observed anisotropic self-assembly of PGNP into superstructures can thus be understood through simple geometric considerations of single patch models, in the same spirit as the geometry-based surfactant models of Israelachvili.

A computer simulation of the networked structure of a hydrogel prepared from a tetra-armed star pre-polymer.

We used a coarse-grained (CG) molecular dynamics model with potentials convertible to actual units to simulate the polymerization of a gel of a tetra-armed poly(ethylene glycol) derivative (MW ≈ 6000) under aqueous conditions and analysed its three-dimensional network structure. The radius of gyration of individual pre-polymers after gelation was slightly increased compared with that of the single pre-polymer before gelation, and its distribution was broad, attributable to inter- and intra-molecular bonds. The largest pores in the unit cell were about 3.5-3.9 nm. The existence of large pores seems to explain the protein encapsulation capability of and protein leakage from the gel indicating that the CG simulation, which maintains information about potentials in actual units, is an effective tool for investigating gel properties that are difficult to measure in real experiments.

Mechanical properties of tetra-PEG gels with supercoiled network structure.

We investigate the effects of swelling and deswelling on the mechanical properties of tetra-polyethylene glycol gels with the precisely tuned polymerization degree of network strand (Nc) and polymer volume fraction at preparation (ϕ0) by varying the fraction of interest (ϕm). The ϕm-dependence of the elastic modulus exhibits a crossover at ϕc due to large contraction of the network strands (supercoiling) accompanying deswelling. The Obukhov model successfully describes the ϕm-dependence of the elastic modulus. We estimate the fractal dimension of network strands (Df) by analyzing the stress-elongation relationships at high stretching using Pincus blob concept. In the supercoiling region, Df increases with an increase in ϕm, which suggests that the gyration radius of network strands decreases with deswelling in affine manner. The extensibility increases with an increase in ϕm because the deswelling reduces the distance between the neighboring junctions. These findings will help to understand the structure and formation mechanism of supercoiling.

Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer's disease, in rodents and nonhuman primates.

γ-Secretase is the enzyme responsible for the intramembranous proteolysis of various substrates, such as amyloid precursor protein (APP) and Notch. Amyloid-ß peptide 42 (Aß42) is produced through the sequential proteolytic cleavage of APP by ß- and γ-secretase and causes the synaptic dysfunction associated with memory impairment in Alzheimer's disease. Here, we identified a novel cyclohexylamine-derived γ-secretase modulator, {(1R*,2S*,3R*)-3-[(cyclohexylmethyl)(3,3-dimethylbutyl)amino]-2-[4-(trifluoromethyl)phenyl]cyclohexyl}acetic acid (AS2715348), that may inhibit this pathological response. AS2715348 was seen to reduce both cell-free and cellular production of Aß42 without increasing levels of APP ß-carboxyl terminal fragment or inhibiting Notch signaling. Additionally, the compound increased Aß38 production, suggesting a shift of the cleavage site in APP. The inhibitory potency of AS2715348 on endogenous Aß42 production was similar across human, mouse, and rat cells. Oral administration with AS2715348 at 1 mg/kg and greater significantly reduced brain Aß42 levels in rats, and no Notch-related toxicity was observed after 28-day treatment at 100 mg/kg. Further, AS2715348 significantly ameliorated cognitive deficits in APP-transgenic Tg2576 mice. Finally, AS2715348 significantly reduced brain Aß42 levels in cynomolgus monkeys. These findings collectively show the promise for AS2715348 as a potential disease-modifying drug for Alzheimer's disease.

Layered mass geometry: a novel technique to overlay seeds and applicators onto patient geometry in Geant4 brachytherapy simulations.

A problem faced by all Monte Carlo (MC) particle transport codes is how to handle overlapping geometries. The Geant4 MC toolkit allows the user to create parallel geometries within a single application. In Geant4 the standard mass-containing geometry is defined in a simulation volume called the World Volume. Separate parallel geometries can be defined in parallel worlds, that is, alternate three dimensional simulation volumes that share the same coordinate system with the World Volume for geometrical event biasing, scoring of radiation interactions, and/or the creation of hits in detailed readout structures. Until recently, only one of those worlds could contain mass so these parallel worlds provided no solution to simplify a complex geometric overlay issue in brachytherapy, namely the overlap of radiation sources and applicators with a CT based patient geometry. The standard method to handle seed and applicator overlay in MC requires removing CT voxels whose boundaries would intersect sources, placing the sources into the resulting void and then backfilling the remaining space of the void with a relevant material. The backfilling process may degrade the accuracy of patient representation, and the geometrical complexity of the technique precludes using fast and memory-efficient coding techniques that have been developed for regular voxel geometries. The patient must be represented by the less memory and CPU-efficient Geant4 voxel placement technique, G4PVPlacement, rather than the more efficient G4NestedParameterization (G4NestedParam). We introduce for the first time a Geant4 feature developed to solve this issue: Layered Mass Geometry (LMG) whereby both the standard (CT based patient geometry) and the parallel world (seeds and applicators) may now have mass. For any area where mass is present in the parallel world, the parallel mass is used. Elsewhere, the mass of the standard world is used. With LMG the user no longer needs to remove patient CT voxels that would include for example seeds. The patient representation can be a regular voxel grid, conducive to G4NestedParam, and the patient CT derived materials remain exact, avoiding the inaccuracy of the backfilling technique. Post-implant dosimetry for one patient with (125)I permanent seed implant was performed using Geant4 version 9.5.p01 using three different geometrical techniques. The first technique was the standard described above (G4PVPlacement). The second technique placed patient voxels as before, but placed seeds with LMG (G4PVPlacement+LMG). The third technique placed patient voxels through G4NestedParam and seeds through LMG (G4NestedParam+LMG). All the scenarios were calculated with 3 different image compression factors to manipulate the number of voxels. Additionally, the dosimetric impact of the backfilling technique was investigated for the case of calcifications in close proximity of sources. LMG eliminated the need for backfilling and simplified geometry description. Of the two LMG techniques, G4PVPlacement+LMG had no benefit to calculation time or memory use, actually increasing calculation time, but G4NestedParam+LMG reduced both calculation time and memory. The benefits of G4NestedParam+LMG over standard G4PVPlacement increased with increasing voxel numbers. For the case of calcifications in close proximity to sources, LMG not only increased efficiency but also yielded more accurate dose calculation than G4PVPlacement. G4NestedParam in combination with LMG present a new, efficient approach to simulate radiation sources that overlap patient geometry. Cases with brachytherapy applicators would constitute a direct extension of the method.

Poly(styrene)-based graded-index plastic optical fiber for home networks.

We investigated poly(styrene) (PSt)-based graded-index plastic optical fiber (GI-POF) with low loss and high bandwidth for home networks. To install the GI-POF in home networks, the attenuation must be below 200 dB/km at a 670-680 nm wavelength, and the bandwidth must be over 2.0 GHz for the 50 m fiber. In this study, we selected a dibenzothiophene (DBT) as a dopant to PSt, and we fabricated PSt-DBT-based GI-POF. We confirmed that the PSt-DBT-based GI-POF has high bandwidth (4.4 GHz) for 50 m fiber and low loss (166-193 dB/km) at a 670-680 nm wavelength and obtained the GI-POF that satisfied the requirements for home networks.

Donepezil- and scopolamine-induced rCMRglu changes assessed by PET in conscious rhesus monkeys.

OBJECTIVE: [(18)F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a useful tool for measuring the regional cerebral metabolic rate of glucose (rCMRglu), which is an index of neuronal activity. Donepezil, an acetylcholine esterase inhibitor (AChEI), has been recommended as a treatment option for patients with Alzheimer's disease (AD). We aimed to characterize the effects of donepezil on rCMRglu using FDG-PET in non-human primates. METHODS: We investigated the effects of administration of donepezil (500 microg/kg, i.m.), the non-selective muscarinic ACh receptor antagonist scopolamine (30 microg/kg, i.m.), and the coadministration of both drugs on the rCMRglu of conscious young rhesus monkeys. RESULTS: Donepezil increased the rCMRglu in all regions of interest except in the thalamus. Scopolamine treatment also increased the rCMRglu in all regions of interest except the cerebellum and thalamus. However, these effects disappeared with coadministration of the drugs. CONCLUSIONS: This PET study showed that administration of donepezil or scopolamine alone increased the rCMRglu in conscious rhesus monkeys. We also found that the donepezil-induced increase was abolished by simultaneous administration of scopolamine, suggesting that muscarinic ACh receptor function plays an important role in the effect of donepezil.

Benchmarking of Monte Carlo simulation of bremsstrahlung from thick targets at radiotherapy energies.

Several Monte Carlo systems were benchmarked against published measurements of bremsstrahlung yield from thick targets for 10-30 MV beams. The quantity measured was photon fluence at 1 m per unit energy per incident electron (spectra), and total photon fluence, integrated over energy, per incident electron (photon yield). Results were reported at 10-30 MV on the beam axis for Al and Pb targets and at 15 MV at angles out to 90 degrees for Be, Al, and Pb targets. Beam energy was revised with improved accuracy of 0.5% using an improved energy calibration of the accelerator. Recently released versions of the Monte Carlo systems EGSNRC, GEANT4, and PENELOPE were benchmarked against the published measurements using the revised beam energies. Monte Carlo simulation was capable of calculation of photon yield in the experimental geometry to 5% out to 30 degrees, 10% at wider angles, and photon spectra to 10% at intermediate photon energies, 15% at lower energies. Accuracy of measured photon yield from 0 to 30 degrees was 5%, 1 s.d., increasing to 7% for the larger angles. EGSNRC and PENELOPE results were within 2 s.d. of the measured photon yield at all beam energies and angles, GEANT4 within 3 s.d. Photon yield at nonzero angles for angles covering conventional field sizes used in radiotherapy (out to 10 degrees), measured with an accuracy of 3%, was calculated within 1 s.d. of measurement for EGSNRC, 2 s.d. for PENELOPE and GEANT4. Calculated spectra closely matched measurement at photon energies over 5 MeV. Photon spectra near 5 MeV were underestimated by as much as 10% by all three codes. The photon spectra below 2-3 MeV for the Be and Al targets and small angles were overestimated by up to 15% when using EGSNRC and PENELOPE, 20% with GEANT4. EGSNRC results with the NIST option for the bremsstrahlung cross section were preferred over the alternative cross section available in EGSNRC and over EGS4. GEANT4 results calculated with the "low energy" physics list were more accurate than those calculated with the "standard" physics list.

Graded-index plastic optical fiber prepared by the coextrusion process.

A graded-index plastic optical fiber (GI POF) has been proposed as the transmission medium to realize high-speed information transmission. We have succeeded in fabricating a GI POF by the dopant diffusion coextrusion process, a method that allows continuous fabrication of GI POF. Although it has been indicated that the refractive index distribution of GI POF fabricated by this process is formed by Fick diffusion with the diffusion coefficient dependent on dopant concentration, the method to control it remains unknown. The purposes of this study are to establish the technology of stable fabricating of GI POF by the coextrusion process and to analyze the bandwidth.

Monte Carlo simulation of large electron fields.

Two Monte Carlo systems, EGSnrc and Geant4, the latter with two different 'physics lists,' were used to calculate dose distributions in large electron fields used in radiotherapy. Source and geometry parameters were adjusted to match calculated results to measurement. Both codes were capable of accurately reproducing the measured dose distributions of the six electron beams available on the accelerator. Depth penetration matched the average measured with a diode and parallel-plate chamber to 0.04 cm or better. Calculated depth dose curves agreed to 2% with diode measurements in the build-up region, although for the lower beam energies there was a discrepancy of up to 5% in this region when calculated results are compared to parallel-plate measurements. Dose profiles at the depth of maximum dose matched to 2-3% in the central 25 cm of the field, corresponding to the field size of the largest applicator. A 4% match was obtained outside the central region. The discrepancy observed in the bremsstrahlung tail in published results that used EGS4 is no longer evident. Simulations with the different codes and physics lists used different source energies, incident beam angles, thicknesses of the primary foils, and distance between the primary and secondary foil. The true source and geometry parameters were not known with sufficient accuracy to determine which parameter set, including the energy of the source, was closest to the truth. These results underscore the requirement for experimental benchmarks of depth penetration and electron scatter for beam energies and foils relevant to radiotherapy.

Synergistic effects of adenosine A2A antagonist and L-DOPA on rotational behaviors in 6-hydroxydopamine-induced hemi-Parkinsonian mouse model.

In this study, we examined the combination effects of L-DOPA and adenosine receptor antagonists on rotational behaviors in a hemi-Parkinsonian mouse model induced by unilateral 6-hydroxydopamine (6-OHDA) injection. The adenosine A(2A) antagonist SCH-58261, but not the A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine or A(2B)-receptor antagonist alloxazine, synergistically potentiated the L-DOPA-induced rotational behaviors in the 6-OHDA-lesioned mice. In addtion, the 6-OHDA-induced lesions of the dopaminergic system did not affect the in vivo binding of an adenosine A(2A)-receptor tracer [(11)C]SCH-442416 in the striatatum. These findings suggest that adenosine A(2A) antagonists are extremely useful for pharmacotherapy of L-DOPA in Parkinson's disease patients.