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.

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion.

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Addressing phototoxicity observed in a novel series of biaryl derivatives: discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.

We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.

Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition.

A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.

Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.

Synthesis and in vivo evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors.

A novel class of phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability in mouse liver microsomes were designed and synthesized starting from 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (MP-10). Replacement of the phenoxymethyl part of MP-10 with an oxymethyl phenyl unit led to the identification of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (14), which showed moderate PDE10A inhibitory activity with improved metabolic stability in mouse and human liver microsomes over MP-10. Compound 14 showed high concentrations in plasma and brain after intraperitoneal administration and dose-dependently attenuated the hyperlocomotion induced by phencyclidine in mice, and oral administration of 14 (0.1, 0.3 mg/kg) also improved visual-recognition memory impairment in mice.

Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition.

A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.

Chronic subdural electrocorticography in nonhuman primates by an implantable wireless device for brain-machine interfaces.

Background: Subdural electrocorticography (ECoG) signals have been proposed as a stable, good-quality source for brain-machine interfaces (BMIs), with a higher spatial and temporal resolution than electroencephalography (EEG). However, long-term implantation may lead to chronic inflammatory reactions and connective tissue encapsulation, resulting in a decline in signal recording quality. However, no study has reported the effects of the surrounding tissue on signal recording and device functionality thus far. Methods: In this study, we implanted a wireless recording device with a customized 32-electrode-ECoG array subdurally in two nonhuman primates for 15 months. We evaluated the neural activities recorded from and wirelessly transmitted to the devices and the chronic tissue reactions around the electrodes. In addition, we measured the gain factor of the newly formed ventral fibrous tissue in vivo. Results: Time-frequency analyses of the acute and chronic phases showed similar signal features. The average root mean square voltage and power spectral density showed relatively stable signal quality after chronic implantation. Histological examination revealed thickening of the reactive tissue around the electrode array; however, no evident inflammation in the cortex. From gain factor analysis, we found that tissue proliferation under electrodes reduced the amplitude power of signals. Conclusion: This study suggests that subdural ECoG may provide chronic signal recordings for future clinical applications and neuroscience research. This study also highlights the need to reduce proliferation of reactive tissue ventral to the electrodes to enhance long-term stability.

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.

Electrocorticographic effects of acute ketamine on non-human primate brains.

Objective. Acute blockade of glutamate N-methyl-D-aspartate receptors by ketamine induces symptoms and electrophysiological changes similar to schizophrenia. Previous studies have shown that ketamine elicits aberrant gamma oscillations in several cortical areas and impairs coupling strength between the low-frequency phase and fast frequency amplitude, which plays an important role in integrating functional information.Approach. This study utilized a customized wireless electrocorticography (ECoG) recording device to collect subdural signals from the somatosensory and primary auditory cortices in two monkeys. Ketamine was administered at a dose of 3 mg kg-1(intramuscular) or 0.56 mg kg-1(intravenous) to elicit brain oscillation reactions. We analyzed the raw data using methods such as power spectral density, time-frequency spectra, and phase-amplitude coupling (PAC).Main results. Acute ketamine triggered broadband gamma and high gamma oscillation power and decreased lower frequencies. The effect was stronger in the primary auditory cortex than in the somatosensory area. The coupling strength between the low phase of theta and the faster amplitude of gamma/high gamma bands was increased by a lower dose (0.56 mg kg-1iv) and decreased with a higher dose (3 mg kg-1im) ketamine.Significance. Our results showed that lower and higher doses of ketamine elicited differential effects on theta-gamma PAC. These findings support the utility of ECoG models as a translational platform for pharmacodynamic research in future research.

Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment.

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.

Enhancing Clinical Trials Through Synergistic Gamma Power Analysis.

While the etiology of many neuropsychiatric disorders remains unknown, increasing evidence suggests that aberrant sensory processing plays a central role. For this class of disorders, which are characterized by affective, cognitive, and behavioral symptoms, electroencephalography remains the dominant tool for providing insight into the physiological and molecular underpinnings of the disease state and predicting the effectiveness of investigational new drugs. Within the spectrum of electrical activity present in the CNS, high-frequency oscillations in the gamma band are frequently altered in these patient populations. Measurement of gamma oscillation can be further classified into baseline and evoked, each of which offers a specific commentary on disease state. Baseline gamma analysis provides a surrogate of pharmacodynamics and predicting the time course effects of clinical candidate drugs, while alterations in evoked (time-locked) gamma power may serve as a disease biomarker and have utility in assessing patient response to new drugs. Together, these techniques offer complimentary methods of analysis for discrete realms of clinical and translational medicine. In terms of drug development, comprehensive analysis containing aspects of both baseline and evoked gamma oscillations may prove more useful in establishing better workflow and more accurate criteria for the testing of investigational new drugs.

Effects of (+)-bicuculline, a GABAa receptor antagonist, on auditory steady state response in free-moving rats.

Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as for their capacity to generate synchronous activity in both human and animal models. Furthermore, abnormal gamma oscillations on ASSR are typically observed in patients with schizophrenia (SZ). Changes in neural synchrony may reflect aberrations in cortical gamma-aminobutyric acid (GABA) neurotransmission. However, GABA's impact and effects related to ASSR are still unclear. Here, we examined the effect of a GABAa receptor antagonist, (+)-bicuculline, on ASSR in free-moving rats. (+)-Bicuculline (1, 2 and 4 mg/kg, sc) markedly and dose-dependently reduced ASSR signals, consistent with current hypotheses. In particular, (+)-bicuculline significantly reduced event-related spectral perturbations (ERSPs) at 2 and 4 mg/kg between 10 and 30 minutes post-dose. Further, bicuculline (2 and 4 mg/kg) significantly and dose-dependently increased baseline gamma power. Furthermore, the occurrence of convulsions was consistent with the drug's pharmacokinetics. For example, high doses of (+)-bicuculline such as those greater than 880 ng/g in the brain induced convulsion. Additionally, time-dependent changes in ERSP with (+)-bicuculline were observed in accordance with drug concentration. This study partially unraveled the contribution of GABAa receptor signals to the generation of ASSR.

Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome.

Fragile X syndrome (FXS) is characteristically displayed intellectual disability, hyperactivity, anxiety, and abnormal sensory processing. Electroencephalography (EEG) abnormalities are also observed in subjects with FXS, with many researchers paying attention to these as biomarkers. Despite intensive preclinical research using Fmr1 knock out (KO) mice, an effective treatment for FXS has yet to be developed. Here, we examined Fmr1-targeted transgenic rats (Fmr1-KO rats) as an alternative preclinical model of FXS. We characterized the EEG phenotypes of Fmr1-KO rats by measuring basal EEG power and auditory steady state response (ASSR) to click trains of stimuli at a frequency of 10-80 Hz. Fmr1-KO rats exhibited reduced basal alpha power and enhanced gamma power, and these rats showed enhanced locomotor activity in novel environment. While ASSR clearly peaked at around 40 Hz, both inter-trial coherence (ITC) and event-related spectral perturbation (ERSP) were significantly reduced at the gamma frequency band in Fmr1-KO rats. Fmr1-KO rats showed gamma power abnormalities and behavioral hyperactivity that were consistent with observations reported in mouse models and subjects with FXS. These results suggest that gamma power abnormalities are a translatable biomarker among species and demonstrate the utility of Fmr1-KO rats for investigating drugs for the treatment of FXS.

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.

A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia.

The gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABAB receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABAB receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABAB receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABAB receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABAB receptor agonists in patients with FM.

Auditory Steady State Response; nature and utility as a translational science tool.

The auditory steady-state response (ASSR) has been used to detect auditory processing deficits in patients with psychiatric disorders. However, the methodology of ASSR recording from the brain surface has not been standardized in preclinical studies, limiting its use as a translational biomarker. The sites of maximal ASSR in humans are the vertex and/or middle frontal area, although it has been suggested that the auditory cortex is the source of the ASSR. We constructed and validated novel methods for ASSR recording using a switchable pedestal which allows ASSR recording alternatively from temporal or parietal cortex with a wide range of frequencies in freely moving rats. We further evaluated ASSR as a translational tool by assessing the effect of ketamine. The ASSR measured at parietal cortex did not show clear event-related spectral perturbation (ERSP) or inter-trial coherence (ITC) in any frequency bands or a change with ketamine. In contrast, the ASSR at temporal cortex showed clear ERSP and ITC where 40 Hz was maximal in both gamma-band frequencies. Ketamine exerted a biphasic effect in ERSP at gamma bands. These findings suggest that temporal cortex recording with a wide frequency range is a robust methodology to detect ASSR, potentially enabling application as a translational biomarker in psychiatric and developmental disorders.

Brain adenosine A2A receptor occupancy by a novel A1/A2A receptor antagonist, ASP5854, in rhesus monkeys: relationship to anticataleptic effect.

UNLABELLED: The purpose of the present study was to measure adenosine A(2A) receptor (A(2A)R) occupancy in the brain by a novel adenosine A(1)/A(2A) antagonist, 5-[5-amino-3-(4fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), and to determine the degree of receptor occupancy necessary to inhibit haloperidol-induced catalepsy in rhesus monkeys. METHODS: A(2A)R occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using an A(2A)R-specific radiotracer, (11)C-SCH442416, and PET in conscious rhesus monkeys. A(2A)R occupancy was monitored after a single intravenous administration of ASP5854 in 3 animals, and a dynamic PET scan was performed at 1, 4, and 8 h after an intravenous bolus injection of the tracer for approximately 740 MBq. Catalepsy was induced by haloperidol (0.03 mg/kg, intramuscularly) and examined for incidence and duration. RESULTS: ASP5854 dose-dependently increased A(2A)R occupancy in the striatum and showed long-lasting occupancy even after the reduction of plasma concentration. Haloperidol induced severe catalepsy at 40 min after intramuscular injection. The incidence and duration of cataleptic posture were dose-dependently reduced by ASP5854 at 1 h after oral administration, and the minimum ED(50) value was 0.1 mg/kg. Administration of a dose of 0.1 mg/kg yielded a plasma concentration of 97 +/- 16.3 ng/mL, which corresponded to 85%-90% of A(2A)R occupancy. CONCLUSION: These results showed that ASP5854 antagonized A(2A)R in the striatum, and the dissociation from A(2A)R was relatively slow. In addition, more than 85% A(2A)R occupancy by ASP5854 resulted in an inhibition of haloperidol-induced catalepsy. Thus, such a pharmacodynamic study directly demonstrates both the kinetics of a drug in the brain and the relationship between dose-dependent receptor occupancy and plasma level.

A novel adenosine A(1) and A(2A) receptor antagonist ASP5854 ameliorates motor impairment in MPTP-treated marmosets: comparison with existing anti-Parkinson's disease drugs.

Recent evidence indicates that adenosine A(2A) receptor antagonists hold therapeutic potential for the treatment of Parkinson's disease (PD). A study on the novel adenosine A(1) and A(2A) receptor dual antagonist 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854) showed it to be effective in various rodents models of PD and cognition. In the present study, we further investigated the potential of ASP5854 as an anti-PD drug using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, which is a highly predictive model of clinical efficacy in PD, and compared its effect with those of existing anti-PD drugs. ASP5854 significantly and dose-dependently improved the total motor disability score for 7h at doses higher than 1mg/kg, and significantly increased total locomotor activity at doses higher than 0.1mg/kg without adverse effects. l-3,4-Dihydroxyphenylalanine+benserazide and bromocriptine also significantly improved the motor disability score and the hypolocomotion caused by MPTP treatment in a dose-dependent fashion. This amelioration was significant at 32+8 and 10-32 mg/kg, respectively, although bromocriptine induced severe emesis. Trihexiphenidyl also significantly improved the total motor disability score at doses of 10-32 mg/kg; however, while a significant increase in the total locomotor activity was observed at 10mg/kg, the drug induced ataxia-like behavior at 32 mg/kg. On the other hand, neither selegiline nor amantadine improved the total motor disability and hypolocomotion. These data substantiate the evidence that the novel adenosine antagonist ASP5854 exerts comparable anti-PD activity with existing anti-PD drugs, which indicates that ASP5854 might have potential to ameliorate motor deficits in PD.