Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230.

Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a "tonic block" mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.

Effect of dopamine receptor-related compounds on naïve common marmosets for auditory steady-state response.

Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is presumed that drugs do not directly affect ASSRs because its abnormalities are associated with schizophrenia. Therefore, to investigate the direct effect of drugs on ASSRs, we established an ASSR evaluation system for common marmosets in a naïve state. Dopamine D1 receptor stimulation (SKF-81297, 2 mg/kg ip) significantly increased evoked power (EP) at 40 Hz. The phase locking factor (PLF) was increased significantly at 20, 30, 40, and 80 Hz. However, administration of a dopamine D1 receptor antagonist (SCH-39166, 0.3 mg/kg ip) resulted in a significant decrease in EP and PLF at 30 Hz. Dopamine D2 receptor stimulation (quinpirole, 1 mg/kg im) tended to increase EP and induced power (IP) at all frequencies, and a significant difference was observed at 30 Hz IP. There was no change in PLF at all frequencies. In addition, dopamine D2 receptor blockade (raclopride, 3 mg/kg ip) reduced EP and PLF at 30 Hz. Subcutaneous administration of the serotonin dopamine antagonist, risperidone (0.3 mg/kg), tended to increase IP and decrease PLF, but not significantly. Taken together, it is possible to compare the differences in the mode of action of drugs on ASSRs using naïve nonhuman primates.NEW & NOTEWORTHY We measured the effects of dopamine receptor-related compounds on ASSR in marmosets. D1 receptor stimulation increased the phase locking factor (PLF) and evoked power (EP), and reduced the induced power (IP). D2 receptor stimulation increased the IP. D1 and D2 receptor blockers reduced the PLF and EP at 30 Hz. Different modes of action of various drugs related to psychiatric disorders were evaluated by administering antipsychotic drugs to naïve marmosets.

Risperidone on apomorphine-induced stereotyped behavior and auditory sensory gating in rhesus monkeys.

The ameliorating effect of risperidone on apomorphine-induced stereotyped behavior and inhibition of auditory sensory gating was investigated using rhesus monkeys. The total duration of the stereotyped behavior observed in the control group was 43.7 ± 23.0 s (n = 3) between 10 and 25 min after vehicle administration, whereas the duration in the apomorphine-treated (0.1 or 0.15 mg/kg i.m., n = 3) group was observed to be significantly prolonged to 413.0 ± 150.6 s. Administration of 0.01, 0.03, 0.1 mg/kg of risperidone 60 min before apomorphine, significantly reduced the duration of this apomorphine-induced stereotyped behavior to 327 ± 104.9 s (n = 3), 8.3 ± 4.2 s (n = 3), and 0.0 ± × 0.0 s (n = 3, t-test: p < 0.05), respectively. Next, the auditory sensory gating test/conditioning (T/C) ratio was used as a bio-marker. The T/C ratio was 0.598 ± 0.0802 in the vehicle-administered control group (n = 4) and was significantly increased to 2.098 ± 0.254 (n = 4) by apomorphine (0.15 mg/kg, i.m.). Administering of risperidone (0.1 mg/kg, s.c.) 30 min before apomorphine treatment significantly restricted the T/C ratio to 0.571 ± 0.0886 (n = 4), compared to the T/C ratio in the vehicle-administered control group. The above results demonstrate, not only behaviorally but also electrophysiologically, the ameliorating effect of risperidone on the induction of schizophrenia-like symptoms by apomorphine in non-human primates.

A novel phosphodiesterase 1 inhibitor reverses L-dopa-induced dyskinesia, but not motivation deficits, in monkeys.

The enzyme phosphodiesterase 1 (PDE1) is highly expressed in the striatum and cortex. However, its role in corticostriatal function has not been fully investigated. The present study was aimed at evaluating the therapeutic potential of PDE1 inhibitors in treating motivation deficits and 3,4-dihydroxy-L-phenylalanine (L-dopa)-induced dyskinesia, which are pathological conditions of the corticostriatal system. We used a novel PDE1 inhibitor 3-ethyl-2-{[trans-4-(methoxymethyl)cyclohexyl]oxy}-7-(tetrahydro-2H-pyran-4-yl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-143136), which was identified in our drug discovery program. Motivation in monkeys was measured using a progressive ratio task. L-Dopa-induced dyskinesia and disability scores were measured in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. DSR-143136 had a high selectivity for PDE1 over other PDE families and 67 other biologic targets. A dopamine D1 receptor antagonist SCH-39166 at 0.01, 0.03 and 0.1 mg/kg potently decreased motivation in monkeys. However, DSR-143136 at 0.3 and 3 mg/kg did not affect motivation deficits induced by low-dose SCH-39166 (0.01 mg/kg). On the other hand, DSR-143136 at 3 mg/kg potently decreased L-dopa-induced dyskinesia in the Parkinsonian monkey model. Importantly, this antidyskinesic efficacy was NOT accompanied by detrimental effects on motor function. Further, this compound decreased on-time with marked or severe dyskinesia, without affecting on-time itself. These findings suggest that PDE1 inhibitor could be a therapeutic candidate for treating L-dopa-induced dyskinesia in Parkinson's disease, but not for motivation deficits.

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia.

In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT: This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.

[Translational behavioral research using common marmosets in the psychiatric field].

The drug discovery activities for novel compounds with the superior efficacies to current drugs have been largely unsuccessful in the psychiatric field. One of the main reasons is the lack of appropriate behavioral assays and animal models for psychiatric disorders. Since the prefrontal cortex has great roles in their pathophysiology, non-human primate common marmosets with the well-developed prefrontal cortex would be useful as experimental animals in the future translational research. To measure objectively and quantitatively the psychiatric symptoms like motivational deficits, negative affective bias and cognitive impairments in patients with schizophrenia or major depressive disorder, the clinical laboratory tasks have been developed. The development of marmoset behavioral paradigms, which may correspond to the clinical laboratory tasks, have been progressed for the translational research. On the other hand, there are still limitations to develop the marmoset models resembling the pathophysiology of psychiatric disorders. We review the current state and future perspective of translational behavioral research using marmosets.

Blockade of dopamine D1 receptors, but not D2 receptors, decreases motivation in a novel effort-discounting paradigm in common marmosets.

Effort-based decision-making paradigms have recently been used to measure motivation in healthy subjects and patients with neuropsychiatric disorders. In the present study, we developed a novel effort-discounting paradigm using a touch-panel system in common marmosets. Marmosets were trained to choose between a low-reward (a piece of cake) requiring low-effort (one touch response) versus high-reward (three pieces of cake) requiring one of three different effort levels (one, two, or four touch responses). Because the number of trials per session was kept constant, the selection of the high-reward choice was always the optimal strategy to receive the maximum number of rewards. Marmosets' high-reward rates were reduced as the physical effort requirement was increased, when they were tested using effort discounting in either ascending or descending order of effort intensity. It indicates that marmosets' decisions could be attributable to cost-benefit evaluation, but not to their fatigue or satisfaction with the reward during the progression of the paradigm. The high dose of dopamine D1 receptor antagonist SCH-39166 (0.03 mg/kg) reduced the high-reward choice rate, only when more effort was required to obtain the high-reward than the low-reward. On the other hand, the D2 receptor antagonist raclopride (0.01 and 0.03 mg/kg) unexpectedly did not affect the high-reward choice rate, but the high dose did increase omission rate. Our finding suggests that dopamine D1 receptor signaling may play a more important role in effort-based decision making than D2 receptor signaling in marmosets. Our novel behavioral paradigm would be useful in translational research focused on motivational deficits. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

An eye tracking system for monitoring face scanning patterns reveals the enhancing effect of oxytocin on eye contact in common marmosets.

Eye tracking systems are used to investigate eyes position and gaze patterns presumed as eye contact in humans. Eye contact is a useful biomarker of social communication and known to be deficient in patients with autism spectrum disorders (ASDs). Interestingly, the same eye tracking systems have been used to directly compare face scanning patterns in some non-human primates to those in human. Thus, eye tracking is expected to be a useful translational technique for investigating not only social attention and visual interest, but also the effects of psychiatric drugs, such as oxytocin, a neuropeptide that regulates social behavior. In this study, we report on a newly established method for eye tracking in common marmosets as unique New World primates that, like humans, use eye contact as a mean of communication. Our investigation was aimed at characterizing these primates face scanning patterns and evaluating the effects of oxytocin on their eye contact behavior. We found that normal common marmosets spend more time viewing the eyes region in common marmoset's picture than the mouth region or a scrambled picture. In oxytocin experiment, the change in eyes/face ratio was significantly greater in the oxytocin group than in the vehicle group. Moreover, oxytocin-induced increase in the change in eyes/face ratio was completely blocked by the oxytocin receptor antagonist L-368,899. These results indicate that eye tracking in common marmosets may be useful for evaluating drug candidates targeting psychiatric conditions, especially ASDs.

Effects of the 5-HT1A receptor agonists buspirone and 8-OH-DPAT on pupil size in common marmosets.

As pupil size is affected by psychotropic drugs in all mammals, it has been used as a well-established clinical indicator for the preclinical and clinical development of novel drugs. It has been reported that activation of the serotonin (5-HT)1A receptor differently affects pupil response in rodents (mydriasis) and humans (miosis). Thus, it is important to establish a quantitative system for measuring pupil size using other species, such as nonhuman primates. Common marmosets have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field because of handling ease compared with other nonhuman primates and the requirement for small amounts of test drugs. In this study, we constructed a system for measuring changes in pupil size using an infrared eye-tracking camera and evaluated the effects on pupil size of the 5-HT1A receptor agonists buspirone, 8-OH-DPAT and buspirone active metabolite 1-(2-pyrimidinyl) piperazine. Our results show that both buspirone and 8-OH-DPAT significantly decrease pupil size in a dose-dependent manner. The 5-HT1A receptor antagonist WAY 100635 completely blocked both buspirone and 8-OH-DPAT-induced miosis, whereas 1-(2-pyrimidinyl) piperazine had no effect on pupil size. These results suggest that measurement of pupil size may be a useful biomarker for predicting the pharmacodynamics of new 5-HT1A receptor agonists.

Advanced lipid technology.

Phospholipids and cholesterols are being spotlighted as raw materials for preparing liposomes, one of the key compounds for drug delivery systems (DDS), and as base compounds for converting water-soluble drugs to fat-soluble drugs. Other applications of phospholipids also are being explored. Nippon Fine Chemical, aware of the future of such lipids, has developed new processes for synthesizing and purifying phospholipids and is supplying them on an industrial scale. These products - used worldwide - are highly regarded as raw materials for preparing liposomes. In particular, Nippon Fine Chemical's innovative research led to the development of "Presome®", a base agent that facilitates the preparation of liposome solutions. To further this research, Nippon Fine Chemical has established an "Advanced Lipid Technology".

The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets.

Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.

The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics.

Behavioral and neurophysiological effects of Ro 10-5824, a dopamine D4 receptor partial agonist, in common marmosets.

RATIONALE: Growing evidence suggests that dopamine D4 receptors (D4Rs) are involved in controlling executive functions. We have previously demonstrated that Ro 10-5824, a D4R partial agonist, improves the performance of common marmosets in the object retrieval detour (ORD) task. However, the neural mechanisms underlying this improvement are unknown. OBJECTIVES: We investigated the behavioral and neurophysiological effects of Ro 10-5824 in common marmosets. METHODS: The effects of Ro 10-5824 on cognitive function were evaluated using the ORD task. The neurophysiological effects of Ro 10-5824 were investigated by quantitative electroencephalography, especially on baseline gamma band activity in the frontal cortex. The effects of Ro 10-5824 on spontaneous locomotion were also assessed. RESULTS: Systemic administration of Ro 10-5824 at 3 mg/kg significantly increased the success rate in the ORD task. At doses of 1 and 3 mg/kg, Ro 10-5824 increased baseline gamma band activity in the frontal cortex. Ro 10-5824 had no effect on spontaneous locomotion. CONCLUSIONS: Activation of D4R by Ro 10-5824 improves the success rate in the ORD task and increases baseline gamma band activity in the frontal cortex without affecting locomotion in common marmosets. These findings highlight the role of D4R in gamma oscillations of non-human primates. As gamma oscillations are thought to be involved in attention and behavioral inhibition, our results suggest D4R agonists may improve these cognitive functions by modulating baseline gamma band activity in the frontal cortex.

The serotonin 5-HT1A receptor agonist tandospirone improves executive function in common marmosets.

Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1-0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1-0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor.

Lurasidone suppresses rapid eye movement sleep and improves sleep quality in rats.

Patients with psychiatric disorders, including schizophrenia, are reported to suffer from sleep disorders. In this study, we investigated the effects of lurasidone, an atypical antipsychotic, on sleep architecture in rats using sleep electroencephalography. The course of sleep in rats was classified into 3 stages: WAKE, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Lurasidone shortened REM duration and prolonged the mean duration of one bout in WAKE and NREM. Quantitative frequency band analysis during NREM sleep revealed that lurasidone increases slow waves and decreases fast waves. These results suggest that lurasidone ameliorates sleep disorders associated with psychosis.

Effects of lurasidone on ketamine-induced joint visual attention dysfunction as a possible disease model of autism spectrum disorders in common marmosets.

Infants with autism have difficulties performing joint visual attention (JVA), defined as following another person's pointing gesture and gaze. Some non-human primates (NHPs) can also perform JVA. Most preclinical research on autism spectrum disorders (ASD) has used rodents as animal models of this social interaction disorder. However, models using rodents fail to capture the complexity of social interactions that are disrupted in ASD. Therefore, JVA impairment in NHPs might be a more useful model of ASD. The aim of this study was to develop an appropriate and convenient ASD model with common marmosets. We first tested whether marmosets were capable of performing JVA. Subsequently, we administered ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, to induce JVA impairment and investigated the effects of lurasidone, a newer antipsychotic agent, on the JVA impairments. An apparatus was constructed using 4 white boxes, which were attached to the corners of a frame. All boxes had a hinged door, and marmosets could easily obtain a reward by pushing the door. An experimenter pointed and gazed at the boxes to inform the marmosets which box contained the reward. Their behavior was scored according to the number of incorrect choices. The JVA score was significantly higher in the cued vs. uncued tasks. Ketamine significantly decreased the JVA score, but lurasidone significantly reversed this effect. These findings suggest that this experimental system could be a useful animal model of neuropsychiatric disorders characterized by NMDA-receptor signaling, including ASD, and that lurasidone might be effective for some aspects of ASD.

Lack of dopamine D4 receptor affinity contributes to the procognitive effect of lurasidone.

We previously demonstrated among several antipsychotics exhibiting potent dopamine D2 receptor antagonism that only lurasidone, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide hydrochloride, improved performance in the object retrieval detour (ORD) task by marmosets. The mechanisms by which only lurasidone causes enhancements in cognitive function have not yet been established; however, most antipsychotics, except for lurasidone, have been shown to exhibit potent antagonistic activity against the dopamine D4 receptor. The objectives of this study were to evaluate the role of the dopamine D4 receptor on executive function with the selective agonist, Ro10-5824 and antagonist, L-745,870, and elucidate a possible mechanism for the procognitive effect of lurasidone. The effects of these drugs were evaluated in naïve marmosets using the ORD task. Changes in the success rate during the difficult trial in the task were used to assess the cognitive effect of the drugs. Ro10-5824 (0.3-3 mg/kg) increased the success rate in the difficult trial, potentiated the effect of lurasidone, and reversed the cognitive impairment induced by clozapine. Interestingly, the co-administration of L-745,870 with lurasidone decreased the success rate in the difficult trial, whereas the single administration of L-745,870 had no effect. These results suggest that activation of the dopamine D4 receptor may improve executive function, whereas concomitant blockade of dopamine D4 and D2 receptors may have the opposite effect. In addition to the other unique binding profiles of other monoamine receptors, the lack of affinity for the dopamine D4 receptor by lurasidone could also contribute, at least partly, to its cognitive-enhancing effect.

Effects of a dopamine D1 agonist on ketamine-induced spatial working memory dysfunction in common marmosets.

It is considered that functional deficiency of the NMDA receptors in the prefrontal cortex (PFC) is one of the causes of the cognitive impairment observed in schizophrenia. As non-human primates display more developed PFC than rodents, they are considered to be useful experimental animals for improving the predictive validity of models used to discover new drugs for treating cognitive dysfunction. The aim of this study was to develop a convenient model of the cognitive impairment observed in schizophrenia using common marmosets and the CANTAB system and to test whether a full agonist of the dopamine D1 receptor (SKF-81297) was effective against the cognitive impairment induced in this model. We administered the NMDA receptor antagonist ketamine (1.5-16mg/kg, i.m.) to the marmosets to induce cognitive impairment and then evaluated their working memory function using the CANTAB spatial working memory (SWM) test. The marmosets' working memory was impaired by subanesthetic doses of ketamine. Next, we tested the effect of SKF-81297 (3 or 10mg/kg, p.o.) on this ketamine-induced cognitive dysfunction. The marmosets were administered SKF-81297 30min before the ketamine injection. Pretreatment with SKF-81297 reversed the ketamine-induced cognitive deficiency. In this study, we found that a D1 receptor agonist, which has been reported to enhance cognitive function, reversed ketamine-induced cognitive impairment in marmosets, which suggests that our marmoset model could be a useful tool for predicting the clinical efficacy of cognitive-enhancing drugs.

Effects of lurasidone on executive function in common marmosets.

Cognitive impairment is one of the major symptoms of schizophrenia, and is considered largely due to dysfunctions in the prefrontal cortex (PFC). Lurasidone, a novel atypical antipsychotic agent with high binding affinity for dopamine D2, serotonin 5-HT7, 5-HT2A and 5-HT1A receptors has been reported to have superior efficacy in rodents' models of cognitive impairment. However, the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates. In this study, we investigated the effect of lurasidone on executive function, which is one of the cognitive domains, in common marmosets and compared the results to those of other antipsychotics. The effects of lurasidone, haloperidol, olanzapine, risperidone, quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours (ORD) task. Before drug treatment, marmosets' success rates in the easy trial of the test were almost 90%. However, maximum success in the difficult trial of the task reached only 50% after 8 days of training. Haloperidol, olanzapine and risperidone decreased correct performance even in the easy trial of the task. All drugs, except lurasidone, impaired success rate in the difficult trial. On the other hand, lurasidone dose-dependently increased marmosets' success rates in the difficult trial with significant effect at 10mg/kg. In conclusion, we have shown in this study that lurasidone, unlike conventional antipsychotics, improves cognition associated with executive function in common marmosets. These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics.